Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries (Tetrahedron Organic Chemistry)

TETRAHEDRON ORGANIC CHEMISTRY SERIES Series Editors: J E Baldwin, FRS & R M Williams VOLUME 17 Solid -Supported Comb...

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TETRAHEDRON ORGANIC CHEMISTRY SERIES Series Editors: J E Baldwin, FRS & R M Williams

VOLUME 17

Solid -Supported

Combinatorial and Parallel Synthesis of Smal I-Molecu lar-Wei g ht Compound Libraries

Related Pergamon Titles of Interest

BOOKS

Tetrahedron Organic Chemistry Series: CARRUTHERS: Cycloaddition Reactions in Organic Synthesis DEROME: Modern NMR Techniques for Chemistry Research FINET: Ligand Coupling Reactions with Heteroatomic Compounds GAWLEY & AUBI~: Principles of Asymmetric Synthesis HASSNER & STUMER: Organic Syntheses Based on Name Reactions and Un-named Reactions McKILLOP: Advanced Problems in Organic Reaction Mechanisms PERLMUTTER: Conjugate Addition Reactions in Organic Synthesis SESSLER & WEGHORN: Expanded, Contracted & Isomeric Porphyrins SIMPKINS: Sulphones in Organic Synthesis TANG & LEVY: Chemistry of C-Glycosides WILLIAMS: Synthesis of Optically Active Alpha-Amino Acids 2nd Edition* WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry

JOURNALS

BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS Full details of all Elsevier Science pubfications/free specimen copy of any Elsevier Science journal are available on request from your nearest Elsevier Science office

* In Preparation

Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries DANIEL OBRECHT Polyphor Ltd, Zurich and

JOSE M. VILLALGORDO University of Girona

PERGAMON An Imprint of Elsevier Science

ELSEVIER SCIENCE Ltd The Boulevard, Langford Lane Kidlington, Oxford OX5 1GB, UK

Library of Congress Cataloging-in-Publication Data

A catalog record from the Library of Congress has been applied for. British Library Cataloguing in Publication Data A catalogue record from the British Library has been applied for. First Edition 1998 ISBN 0 08 043258 1 Hardcover ISBN 0 08 043257 3 Flexicover

9 1998 Elsevier Science Ltd All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publisher. The paper used in this publication meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper). Printed in the Netherlands.

This book is dedicated to

Sir Jack E. Baldwin (Waynflete Professor of Chemistry, Oxford UK)

and

Prof. Dr. Heinz Heimgartner (University of Ztirich, CH)

This Page Intentionally Left Blank

List of Contributors

Boopathy Dhanapal (BD)

Thierry Masquelin (TM)

Polyphor Ltd.

Pharma Research

Winterthurerstr. 190

F.Hoffmann-La Roche Ltd.

CH-8057 ZUrich

CH-4070 Basel

Wemer Doebelin

Daniel Obrecht (DO)

Prolab/LabSource

Polyphor Ltd.

Zihlackerstr. 4

Winterthurerstr. 190

CH-4153 Reinach

CH-8057 ZiJrich

Philipp Ermert (PE)

Klara Sekanina (KS)

Polyphor Ltd.

Polyphor Ltd.

Winterthurerstr. 190 CH-8057 ZiJrich

Winterthurerstr. 190 CH-8057 Ziirich

Patrick Jeger (PJ) Lipomed AG Fabrikmattenweg

Jose M. Villalgordo (JMV) Departamento de Quimica

CH-4144 Arlesheim

Universitad de Girona

Facultad de Ciencias Campus di Montilivi E- 17071 Girona

Liza Koltay Koltay Design Gustackerstr. 20

Comelia Zumbmnn (CZ)

CH-4103 Bottmingen

Pharma Research F.Hoffmann-La Roche Ltd. CH-4070 Basel


Table of Contents Foreword List of Abbreviations

~

1. Introduction, Basic Concepts and Strategies

1

1.1. Opening remarks (DO)

1

1.2. Historical landmarks in solid-supported organic synthesis (DO)

5

1.3. Applications of solid-supported organic chemistry (DO)

10

1.4. The role of solid-supported chemistry in modern drug discovery (DO)

17

1.4.1. The four key elements of lead finding

17

1.4.2. Sources for novel lead compounds

2o

1.5. Solid supports (PE) 1.5.1. Immobilisation of substrates

24 24

1.5.2. Immobilisation of reagents and catalysts

26

1.5.3. Crosslinked polystyrene-derived matrices

27

1.5.4. Funcfionalised polystyrene resins

29

1.5.4.1. Chloromethylated polystyrenes

30

1.5.4.2. Aminomethylated polystyrene resins

32

1.5.4.3. Various functionalised polystyrene resins 1.5.5. Polyacrylamide resins

33 38

1.5.6. TentaGel | resins

39

1.5.7. Novel polymeric supports

4o

1.6. Solid-supported reagents (PE)

44

1.6.1. Introduction

44

1.6.2. Multipolymer systems

49

1.6.2.1. Insoluble polymeric reagents 1.6.2.2. Soluble and insoluble polymeric reagents

49 52

1.6.3. Application of functionalised polymers to purification

54

1.6.4. Polymer-supported reagents and catalysts

6o

1.6.5. Polymer-supported chiral auxiliaries

79

1.7. Linker molecules and cleavage strategies (BD, DO)

85

1.7.1. Introduction

85

1.7.2. Linker molecules releasing one specific functional group

85

1.7.3. Cyclisation-assisted cleavage

96

1.7.4. Multidirectional cleavage strategies

98

Table of Contents

1.7.4.1. Direct cleavage by nucleophilic substitution

98

1.7.4.2. Multidirectional direct cleavage by electrophiles

100

1.7.4.3. "Safety-catch" linkers

101

1.8. Synthetic strategies in combinatorial and parallel synthesis (DO, TM)

105

1.8.1. Solution- versus solid-phase chemistry

105

1.8.2. Compound mixtures versus single compound collections

106

1.8.3. Parallel and split-mixed synthesis

108

1.8.4. Linear versus convergent strategies

112

1.8.5. Multicomponent and multigeneration reactions

114

1.8.5.1. Multicomponent one-pot reactions

117

1.8.5.2. Multigeneration reactions

123

1.9. Classification of reactive building blocks (DO)

127

1.9.1. Mono- and polyvalent donor building blocks (nucleophiles)

131

1.9.2. Mono- and polyvalent acceptor molecules (electrophiles)

134

1.9.3. Acceptor-donor molecules

136

1.9.4. Acetylenic ketones as typical representatives of a bis-acceptor reactophore

138

1.9.5. Combinatorics of reactive building blocks

142

1.10. Tagging and deconvolution (KS)

145

1.11. Diversity (planning/assessment) (P J)

156

1.12. Analytical methods (P J)

158

1.12.1. Analysis of single compounds in solution

158

1.12.2. Analysis of single compounds on the bead

158

1.12.3. Analysis of compound mixtures

159

1.13. Robotic systems and workstations (DO)

160

References

164

2. Linear Assembly Strategies

185

2.1. Introduction

185

2.2. Peptides

186

2.2.1. General

186

2.2.2 Synthetic approaches to linear peptide libraries

186

2.3. Conformationally constrained peptides

188

2.3.1. Solid-phase synthesis of unnatural amino acids and peptides

189

2.3.2. I]-Turn mimetics

190

2.3.3. Loop mimetics

193

Table of Contents 2.4. Peptoids

197

2.5. Oligonucleotides

200

2.6. Oligosaccharides

201

2.7. Oiigocarbamates and oligoureas

205

2.8. Peptide-Nucleic acids (PNA)

207

References

208

3. Library Synthesis in Solution Using Liquid-Liquid and Liquid-Solid Extractions and Polymer-Bound Reagents (CZ, TM, DO)

213

3.1. General

213

3.2. Applications of solution-phase multicomponent and multigeneration reactions

217

3.2.1. Optimisation of the biological activity using a genetic algorithm

217

3.2.2. Synthesis of heterocycles using amino-azirine building blocks

218

3.2.3. The use of 1-isocyanocyclohexene in Ugi four component condensations

218

3.2.4. Multigeneration synthesis of a thiazole library

220

3.3. Applications of liquid-liquid phase extractions

222

3.3.1. Multigeneration synthesis using an "universal template"

222

3.3.2. Non-aqueous liquid-liquid extraction using fluorinated solvents

222

3.4. Applications of liquid-solid phase extractions and polymer-bound scavengers

224

3.4.1. Solid-phase extraction using ion exchange resins

224

3.4.2. Solid-phase extraction using covalent scavengers

225

3.4.3. Synthesis of a thiazole library using liquid- and solid-phase extractions

226

3.4.4. Synthesis of a pyrazole library using purification by solid phase extraction

227

3.5. Applications of polymer-bound reagents 3.5.1. Polymer-supported Burgessreagent

228 228

3.5.2. Polymer-supported silyl enol ethers

229

3.5.3. Polymer-supported oxazolidinones

230

3.5.4. Polymer-supported tfiphenylphosphines

231

3.5.5. Simultaneous multistep synthesis using several polymer-supported reagents

234

3.6. Applications of polymer-bound catalysts

235

3.6.1. Catalysts for oxidations

235

3.6.2. Catalysts for reductions

238

3.6.3. Catalysts for C-C bond formation

239

3.6.4. Miscellaneous

244

Table of Contents

3.7. Solution chemistry using temporary trapping of intermediates on solid support ("intermediate catch" or "resin capture")

246

3.7.1. Ugi four component condensation using a polymer-bound carboxylic acid

246

3.7.2. Sequential Ugi-4CC and aza-Wittig reaction using a polymer-bound trapping reagent

247

3.7.3. Multistep Suzuki-couplings using resin capture

249

3.7.4. Functionalised polymers as protective groups

251

3.8. Organic synthesis on soluble polymeric supports

252

3.8.1. Introduction

252

3.8.2. Combinatorial synthesis of biopolymers on soluble supports

253

3.8.3. Liquid-phase combinatorial synthesis (LPCS) of small organic molecules

255

References

256

4. C o n v e r g e n t A s s e m b l y Strategies on Solid Supports ( J M V )

259

4.1. Multigeneration assembly strategies with single functional group liberation

259

4.1.1. Liberation of -OH groups

259

4.1.1.1. Synthesis of benzimidazoles

259

4.1.1.2. Synthesis of 1,3-dialkyl quinazolin-2,4-diones

261

4.1.1.3. Synthesis of 1,4-benzodiazepine-2-ones

262

4.1.1.4. Synthesis of pyrrolidines

265

4.1.1.5. Synthesis of aspartic acid protease inhibitors

267

4.1.2. Liberation of-NH 2 groups

269

4.1.2.1. Cyclic ureas and thioureas

269

4.1.2.2. Synthesis of 1,4-dihydropyridines

271

4.1.2.3.2,9-Disubstituted purines

273

4.1.3. Liberation of-COOH groups

275

4.1.3.1. Synthesis of quinolones

275

4.1.3.2. Synthesis of pyridines and pyrido[2,3-b]pyrimidines

277

4.1.3.3. Synthesis of mercaptoacyl prolines

278

4.1.3.4. Synthesis of [~-lactams

280

4.1.3.5. Synthesis of quinazolin-2,4-diones

281

4.1.3.6. Synthesis of dihydro- and tellahydroisoquinolines

283

4.1.4. Liberation of -CONH2 groups

284

4.1.4.1. Synthesis of 3,4-dihydro-2(1H)-quinolinones

284

4.1.4.2. Synthesis of 1,2,3,4-tetrahydroquinoxalin-2-ones

285

4.1.4.3. Synthesis of 1,4-benzodiazepine-2,5-diones

287

4.1.5. Multigeneration assembly strategies with mono-functional liberation of miscellaneous groups 4.1.5.1. Synthesis of substituted 1,2,3-triazoles

289 289

Table of Contents

4.1.5.2. Synthesis of thiophenes and dihydrothiazoles 4.2. Multigeneration assembly strategies using traceless linkers

290 292

4.2.1. Synthesis of 1,4-benzodiazepines

292

4.2.2. Synthesis of furans

296

4.2.3. Synthesis of prostaglandins

298

4.3. Multicomponent assembly strategies with single functional group liberation 4.3.1. Synthesis of imidazoles

300

3OO

4.3.2. Synthesis of proline derivatives

302

4.3.3. Synthesis of 2-arylquinoline-4-carboxylic acid derivatives

3O3

4.3.4. Synthesis of dihydropyrimidines

3O4

4.4. Multigeneration assembly strategies with cyclisation-assisted cleavage 4.4.1. Synthesis of 1,4-benzodiazepine-2,5-diones

306 3O6

4.4.2. Synthesis of benzoisothiazolones

307

4.4.3. Synthesis of pyrazolones

308

4.4.4. Synthesis of hydantoins

310

4.4.5. Synthesis of 5-alkoxyhydantoins

312

4.4.6. Synthesis of 1,3-disubstituted quinazolin-2,4-diones

313

4.4.7. Synthesis of pyrazolo[ 1,5-a]pyrrolo[3,4-d]pyrimidinediones

315

4.4.8. Synthesis of quinazolinones

316

4.5. Muiticomponent assembly strategy with cyclisation-assisted cleavage 4.5.1. Synthesis of diketopiperazines 4.6. Multigeneration assembly strategies with multidirectional cleavage 4.6.1. Without activation of the linker moiety

318 318 319 319

4.6.1.1. Synthesis of ketoureas

319

4.6.1.2. Synthesis of bicyclo[2.2.2]octanes

320

4.6.1.3. Synthesis of cyclopentane and cyclohexane derivatives

321

4.6.2. With activation of the linker moiety ("safety-catch" linkers)

322

4.6.2.1. Synthesis of arylacetic acids

322

4.6.2.2. Synthesis of pyrimidines

323

References

328

Outlook and future directions

334

Subject Index

335

Acknowledgements

339


FOREWORD

The words "Combinatorial Chemistry" have different meanings to different people, ranging from split and mix strategies to parallel synthesis using robots, and embracing the whole range of preparative chemistry from organic molecules, to catalyst ligands, and even inorganic solids. All of these activities have in common an attempt to expand the diversity of structure available to the chemist as well as the access to this diversity, permitting the discovery of new and valuable biological acid material properties. In this outstanding survey of combinatorial organic chemistry the authors Obrecht, who has established a new combinatorial chemistry company called Polyphor, and Villalgardo have brought together the literature, including that from 1998, and have concisely analysed the applications and achievements of th!s new field. This work will be of value to all chemists engaged in preparative work, both in industry and academe.

J E Baldwin, FRS

XV


Abbreviations

List of Abbreviations Ac acac ACD ACE ADP AIBN Ala Arg Asn Asp ATP 9-B BN BHA Bn

acetyl acetylactone available chemicals directory angiotensin converting enzyme adenosine diphosphate azoisobutyronitrile L-alanine L-arginine L-asparagine L-aspartate adenosine triphosphate 9-borabicyclo [3.3.1 ]nonane benzhydrylamine benzyl

Boc

tert-butoxycarbonyl

Bpoc Bu Bz CAE CAN Cbz CNS COD COS Cys DAMGO

2- (4-biphenylyl)isopropyloxycarbonyl butyl benzoyl carbonyl alkyne exchange reaction ceric ammonium nitrate benzyloxycarbonyl central nervous system 1,5-cyclooctadiene combinatorial organic synthesis L-cysteine [D-Ala, MePh4, Gly-015]enkephalin

DBU DCC IX)Q DEAD

1,8-diazabicyclo[5.4.0]-undec-7-ene N,N' -dicyclohexylcarbodiimide 2,3-dichloro-5,6-dicyanobenzoquinone diethyl azodicarboxylate

DIAD

diisopropyl azodicarboxylate

DIBAH DIC DIEA DMA DMAD

diisobutylaluminium hydride N,N' -diisopropylcarbodiimide N,N-diisopropyl-N-ethylamine N,N-dimethylacetamide dimethyl acetylenedicarboxylate

xvii

Abbreviations

DMAP DME DMF DMS DMSO DMT DNA DTBP DVB EDCI ELISA Et

FAB Fmoc FT GABA GC Gin Glu Gly HATU HBTU His HIV HMB HMDS HMP HOBt

HPLC HTS Ile IR

LAH LDA Leu LPCS LPE

Lys

xviii

N,N-dimethylaminopyridine ethylene glycol dimethyl ether N,N-dimethylformamide dimethylsulfide dimethylsulfoxide dimethoxytrityl desoxyribonucleic acid 2,6-di-(tert-butyl)pyridine divinylbenzene 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide enzyme linked immunosorbant assay ethyl fast atom bombardment 9-fluorenylmethoxycarbonyl Fourier transform ),-aminobutyric acid gas chromatography L-glutamine L-glutamate L-glycine azabenzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate 2-(1H-benzotriazole- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate L-histidine human immunodeficiency virus p-(hydroxymethyl)benzoyloxy-methyl hexamethyldisilazane (hydroxymethyl)phenoxy)acetic acid 1-hydroxybenzotriazole high performance liquid chromatography high throughput screening L-isoleucine infrared spectroscopy lithium aluminium hydride lithium N,N-diisopropylamide L-leucine liquid-phase combinatorial synthesis liquid-phase extraction L-lysine

Abbreviations

m-CPBA MALDI-TOF MAS-NMR MBHA Me Met MMP Mpc MS Mtr NBS NGF NMM NMO NMP NMR NVOC PAL PAM PCD PCR PEG

Pfp Ph Phe PNA PPOA PPTS Pro PS PSP PSQ PTBD PVPCC PY PyBOP PyBrOP RAM

m-chloroperbenzoic acid matrix-assisted, laser desorption ionisation time-of-flight MS magic-angle spinning NMR p-methylbenzhydrylamine methyl L-methionine matrix metalloproteinase 2- (4-methylphenyl)isopropyloxycarbonyl mass spectroscopy methoxytrityl N-bromosuccinimide nerve growth factor N-methylmorpholine N-methylmorpholine N-oxide N-methylpyrrolidinone nuclear magnetic resonance N-nitroveratryloxycarbonyl 5-(4-Fmoc-aminomethyl-3,5-dimethoxyphenoxy)valeric acid phenylacetamidomethyl pyridinium dichromate polymerase chain reaction polyethylene glycol pentafluorophenyl phenyl L-phenylalanine peptide-nucleic acid 4-(2-bromopropionyl)-phenoxyacetic acid pyridinium p-toluene sulfonic acid L-proline polystyrene polymer-supported perruthenate polymer-supported quenching procedure polymer-supported 1,5,7-triazabicyclo[4.4.0] dec-5-ene poly(4-vinylpyridinium chlorochromate) pyridine (benzotriazole- 1-yl)-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate bromo-tris-pyrrolidino-phosphonium hexafluorophosphate Rink amide resin

xix

Abbreviations

RNA SCAL Ser SPE SPOS Su TADDOL

ribonucleic acid safety catch amide linkage L-serine solid-phase extraction solid phase organic synthesis succinimidyl t~, t~, t~', t~'-tetraaryl-1,3-dioxolane-4,5-dimethanol

TBAF TBTU TCEP TES Tf TFA TFE THF Thr TIPS TLC TMEDA TMG TMS Trp Ts Tyr UV Val XAL

tetrabutylammonium fluoride O-(benzotriazole- 1-yl)tetramethyluronium tetrafluoroborate tris-(2-carboxyethyl)phosphine triethylsilyl trifluoromethanesulfonyl (triflyl) tfifluoroacetic acid 2,2,2-trifluoroethanol tetrahydrofuran L-threonine triisopropylsilyl thin layer chromatography tetramethylethylenediamine tetramethylguanidine

trimethylsilyl L-tryptophane p-toluolsulfonyl L-tyrosine Ultraviolet spectroscopy L-valine [[9-[(9-fluorenylmethyloxycarbonyl)amino]xanthen-2(or 3)-yl]oxy]alkanoic acid Polystyrene resin (cf. Chapter 1.7, Table 1.7.1)

Wang resin (cf. Chapter 1.7, Table 1.7.1) Sasrin resin (cf. Chapter 1.7, Table 1.7.1)

Rink resin (cf. Chapter 1.7, Table 1.7.1)

XX

Chapter 1

Introduction, Basic Concepts and Strategies 1.1. Opening remarks Friedrich Woehler's discovery of synthetic urea in 1828 was not only the start of synthetic organic chemistry, but was ultimately also the beginning of a change of paradigm in biology, which led finally to molecular biology. 1 Although biopolymers such as proteins, DNA and RNA play a dominant role in living matter, and synthetic polymers derived from polystyrene have been known since 1839, 2 it was only in 1963 when R. B. Merrifield published his seminal paper on solidsupported peptide synthesis 3 that organic synthetic chemists started to consider polymers as valuable tools for synthesis. It is not surprising that polymer-supported synthesis found wide applications in the field of polypeptide and oligonucleotide chemistry as their synthesis consists of linear repetitive cycles of deprotection-, coupling- and washing steps, which ultimately could be fully automated and carried out on robotic systems. In the two decades following Merrifield's pioneering work many other synthetically useful reactions were successfully transferred to mainly polystyrene-derived resins by scientists such as

teznoff4 and Frdchet. 5 It was also recognised by several authors that polymer-bound reagents

and

catalysts 2,5 such as boronic acids, peracids and phosphines might be extremely valuable tools to carry out solution chemistry while keeping all the benefits of solid supports such as simple work up and purification procedures. Additional exciting aspects initiated by the use of polymer-bound reagents such as employing oxidising and reducing agents in the same reaction compartment, were recognised early on 2 but their scope was not fully exploited. Twelve years after MerrifieM's work on polypeptides Rapoport 6 critically reviewed the field of solid-phase organic chemistry by asking: "Solid-phase organic synthesis: Novelty or fundamental concept?" Maybe due to the lack of industrial applications, the interest in solid-supported chemistry somehow slowed down for the next decade and was essentially concentrated on polypeptide and oligonucleotide chemistry. The field of organic synthesis was focusing on the total synthesis of complex natural products, on the elucidation of their biosynthesis and on the development of novel synthetic methodologies. Synthetic organic chemistry quickly reached the level of a "mature" science with the general perception that chemists were now able to synthesise any given smallmolecular-weight natural and synthetic compound no matter how complex the structure would be. 7 A lot of the motivation to synthesise complex molecules such as taxol (Figure 1) has been initiated by the fact that these molecules exhibit interesting biological activities. Thus, the significant

1. Introduction, basic concepts and strategies

progress made in synthetic organic chemistry had direct repercussions in drug discovery in that more and more complex molecules with increasing potency and selectivity could be synthesised, tested and ultimately manufactured successfully. Figure I

O

Ph

O

\

p. N'L-JL, o H

, . , , , ,L A c O ,,,O OH

)-'-~(~ |

....

OH

HO

~BzOAc

1: taxol

The main stream of synthetic organic chemists most often did not incorporate solid supports and solid-supported reagents in their synthetic concepts. For this reason, it was not a surprise that the first ideas for the parallel and combinatorial synthesis of compound libraries emerged from scientists like Geysen 8 and Houghten 9 working in the polypeptide area. While this area offered a lot of potential applications for the use of peptide libraries it was really the dramatic changes in the methods and throughput of biological screening in pharmaceutical and agrochemical research that initiated a literal burst of interest for novel and diverse compound collections.lO, 11 Alongside molecular biology and genomic sciences, which are creating an ever-growing number of new and biologically relevant targets, and providing deeper insights into biological mechanisms and processes, novel high-throughput screening methods offer also the possibility to screen thousands of molecules per day. Hence, there was a real need for a large number of novel small-molecularweight compounds and synthetic chemists were challenged to develop efficient high-throughput synthesis methods. For obvious reasons solid-supported chemistry became, from the nineties on, a fashionable area of research. At the outset chemists focused on known solid-phase methodologies available from peptide- and oligonucleotide chemistry but the shift towards small-molecular-weight compounds necessitated new synthetic strategies. In the early nineties several research groups in academia and industry started extensive programs on transferring solution chemistry to solid supports, 12 developing novel linker and cleavage procedures in order to broaden the scope of molecules amenable on solid supports. Once again polymer-bound reagents and catalysts enjoyed a renaissance because they offered the possibility to carry out reactions in solution while maintaining the advantages of solid supports such as ease of isolation, work-up and purification. 13 While peptide- and oligonucleotide chemists created the prospect of synthesising libraries of millions of molecules, the shift towards small-molecular-weight "drug-like" compounds needed by the agrochemical and pharmaceutical companies initiated a reassessment and redimensioning of the library sizes. From initially mixtures

1.1 Openingremarks of thousands of compounds possible in the field of peptide- and oligonucleotide libraries, necessitating complex tagging and deconvolution strategies, there was a gradual shift towards mixtures of 10-20 members 14 of a given library observable. As solid-supported synthetic strategies became more sophisticated and convergent and thus the resulting products more structurally complex and "drug-like", there was again a shift towards the parallel synthesis of single compounds with a defined chemical purity and confirmed structure. The progress made in the development of efficient workstations and robotic systems for parallel synthesis guaranteeing a high synthetic throughput, the call for small-molecular-weight compounds together with the severe problems resulting from screening of mixtures, were responsible for this dramatic shift in paradigm. Novel synthetic strategies, polymer supports and polymer-supported reagents and catalysts, new linker- and cleavage strategies and new reactive building blocks are now being discovered at high speed, and it is becoming more and more accepted that solid supports offer an new dimension when incorporated into synthetic design strategies. In this book "Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight

Compound Libraries" we focus on the synthetic aspects of polymer-supported chemistry without neglecting related areas such as tagging- and deconvolution aspects, analytical methods and spectroscopy. After some historical landmarks we present a short survey of applications of solid supports followed by the four elements of lead finding and aspects of the drug development process. We then focus on polymer supports and polymer-supported reagents and catalysts used for the synthesis of small-molecular-weight compounds. Forming the connection between the solid support and the actual molecules that are synthesised, the linkers play a crucial role in the synthetic concepts of solid supported synthesis (Chapter 1.7). While in the fields of peptide- and oligonucleotide chemistry the linkers were mainly designed to release one functional group, carbocyclic- and heterocyclic compounds require new resin-releasing techniques such as cleavage by cyclisation and multidirectional cleavage procedures which introduce new elements of diversity in the very last step and allow the production of very pure products. We discuss in Chapter 1.8 the different synthetic strategies amenable to solid-phase chemistry, briefly mention aspects of solution-and solid-phase synthesis, mixtures versus single compound collections and explain the key technologies of parallel and combinatorial chemistry such as the "split-mixed technology". 15 Focusing on convergent strategies we will highlight the importance of multicomponent one-pot and multigeneration reactions as efficient strategies to create small molecule libraries. In all these approaches, reactive building blocks ("reactophores") which are essentially constituted of a reactive group to which are attached orthogonally protected functional groups ready for subsequent easy transformations, play a crucial role. The reactophores are designed to react in simple high yielding one-step transformations to give a large array of interesting core structures ("pharmacophores") which can subsequently be easily transformed into the final molecules. We have classified these reactophores into three categories: donors, acceptors and donor-acceptors. We will discuss the

1. Introduction, basic conceptsand strategies

possibilities to combine these reactophores in multicomponent and multigeneration reactions and comment on the intriguing result that the same set of building blocks can give rise to a multitude of novel core structures depending on the sequence of mixing. Amongst others, building blocks derived from natural products will increasingly be developed with a view to synthesising focused libraries. The "combinatorics of reactophores" thus constitutes a novel interesting dimension in combinatorial and paraUel chemistry. After explaining the terms and strategies of tagging and deconvolution, we will talk about aspects of diversity assessment and planning, library formats, analytical methods used in solid-supported organic chemistry and finally very briefly touch on aspects of robotics and automation. After having explained the rules and the methods used in combinatorial and parallel chemistry we will turn our attention to examples and applications which have appeared in the recent literature, starting with a brief account of linear strategies towards polypetides, peptidomimetics, peptoids, oligonucleotides and oligosaccharides. Focusing much more on convergent approaches towards small molecules, we will first analyse in Chapter 3 examples which have been performed in solution using polymer-supported scavengers, and solid-supported reagents and catalysts, in order to speed up the extraction, work-up and purification procedures. In Chapter 4 we will then concentrate on examples which have been completely performed on solid-phase. In analysing the examples we will always highlight the reactive building blocks, the solid supports, the linkers and the synthetic strategies that have been employed. We have attempted to increase the complexity of the combinatorial elements as we go through the examples presented. Thus, we will conclude with examples combining essentially all useful strategies of combinatorial and parallel chemistry, such as "safety-catch" linkers, highly reactive and versatile building blocks, diversification using multicomponent one-pot and multigeneration approaches with multidirectional resin cleavage procedures. By following this strategy we hope that the reader will get a flavour for where this exciting field is heading and what technologies might emerge in the future. Those people who have tried here to summarise solid-supported organic synthesis in a hopefully clear and comprehensive way agree:

"Solid-supported organic chemistry has only just started to become a new dimension in organic synthesis"

D. Obrecht, April 1998

1.2. Historical landmarksin solid-supportedorganic synthesis

1.2. Historical landmarks in solid-supported organic synthesis Although natural polymers such as cellulose nitrate (1838) and cellulose acetate (1870) were discovered in the last century, and also synthetic polymers derived from styrene (1839), isoprene (1879) and methacrylic acid (1880) have been known for quite some time, it was really H. Staudingers macromolecular theory (1930) that set the stage for a better understanding of polymers. 2 Concerning organic chemistry on polymers, it was definitely R. B. MerrifieM and his fundamental contribution about solid-supported peptide synthesis in 19633 and Letsinger 16 and Khorana's work on oligonucleotide synthesis that inspired and initiated a lot of further investigations. Some of the historical landmarks are mentioned below (this list is by no means complete or representative).

196 3:

Seminal paper by R. B. Merrifield describing for the first time the successful synthesis of a short peptide on a polystyrene resin (J. Am. Chem. Soc. 1963, 85, 2149)

1965:

Letsinger and Khorana applied solid supports for the synthesis of oligonucleosides (J. Am. Chem. Soc. 1965, 87, 3526; ibid. 1966, 88, 3181)

1967:

J. Frdchet described a highly loaded trityl resin (2.0 mmol/g)

1967:

Wilkinson et al. described polymer-bound tris(triphenylphosphine) chlororhodium as hydrogenation catalyst (J. Am. Chem. Soc. 1967, 1574)

1969:

Solid-phase synthesis of Ribonuclease (J. Am. Chem. Soc. 1969, 91,501)

1970:

H. Rapoport introduced the term hyperentropic efficacy (effect of high dilution) on solid supports (J. Am. Chem. Soc. 1970, 92, 6363)

1971:

Frdchet et al. pioneered solid-phase chemistry in the field of carbohydrate research. (J. Am. Chem. Soc. 1971, 93, 492)

1973:

Application of intramolecular Dieckmann-condensation for the solid-phase synthesis of lactones by Rapoport et al. (J. Macromol. Sci. Chem. 1973, 1117)

1973:

Leznoff et al. described the use of polymer supports for the mono-protection of symmetrical dialdehydes, describing oxime formation, Wittig-reaction, crossed aldolcondensation, benzoin-condensation and Grignard- reaction on solid support. (Can. J. Chem. 1973, 51, 3756)


1974:

F. Camps et al. described the first synthesis of benzodiazepines on solid support (Ann. Chim. 1974, 70, 1117)

1976:

Leznoff and Fyles described bromination and lithiation of insoluble polystyrene, thus pioneering the synthesis of functionalised resins

(Can. J. Chem. 1976, 54, 935) 1976:

Rapoport and Crowley published a review entitled: "Solid phase organic synthesis: Novelty or fundamental concept?" and raised three important questions

(Acc. Chem. Res. 1976, 9, 135) 9 degree of separation of resin-bound functionalities 9 analytical methods to follow reactions on solid support 9 nature and kinetics of competing side reactions 19761978:

Leznoff et al. published a series of papers dealing with the synthesis of insect sex attractants (Can. J. Chem. 1977, 55, 1143)

1977:

Wulff et al. synthesised chiral macroporous resins using carbohydrates as templates for the use of column materials for the separation of enantiomers

(Makromol. Chem. 1977, 178, 2799) 1979:

Leznoff employed successfully a chiral linker for the asymmetric synthesis of (S)-2methylcyclohexanone in 95% e.e. (Angew. Chem. 1979, 91,255)

1984:

Geysen et al. described the multi-pin technology for the multiple peptide synthesis (Proc. Natl. Acad. Sci. USA, 1984, 81, 3998)

1985:

Houghten et al. described the tea-bag method for multiple peptide synthesis (Proc. Natl. Acad. Sci. USA, 1985, 82, 5131)

1985:

G.P. Smith described in a seminal paper the use of fdamentous phage for the synthesis of peptide libraries (phage display method, Science, 1985, 228, 1315)

1986:

Mixtures of activated amino acid monomers were coupled to solid supports for the synthesis of peptide libraries as mixtures, the product distribution depending on the relative coupling rates (Mol. Immunol. 1986, 23,709)

1.2. Historical landmarks in solid-supported organic synthesis

1991:

Fodor et al. described the VLSIPS-method (very large scale immobilised polymer

synthesis; photolitographic parallel synthesis (Science, 1991, 251,767)) 1991:

Furka et al. described the "portioning-mixing" method (Int. J. Pept. Prot. Res. 1991, 37, 487), which was termed "split synthesis" by Hruby et al. (Nature 1991, 354, 82)

and "divide, couple, and recombine" process by Houghten et al. (Nature 1991, 354, 84) 1992:

Oligonucleotide-encoded chemical synthesis proposed by Lerner and Brenner (Proc. Natl. Acad. Sci. USA, 1992, 89, 5181)

1992:

Synthesis of 1,4-benzodiazepins on solid support described independently by S. HobbsDeWitt (Diversomer| technology, US 5324483, 1993) and J. A. Ellman (J. Am. Chem. Soc. 1992, 114, 10997)

1993:

Binary encoded synthesis using gas chromatographically detectable chemically inert tags by W. C. Still et al. (Proc. Natl. Acad. Sci. USA, 1993, 90, 10922)

1993:

Use of multi-cleavable linkers for the synthesis of peptide-type libraries by M. Lebl et al. (Int. J. Protein Res. 1993, 41,201)

1994:

Use of the "safety-catch" linker principle developed by Kenner et al. (J. Chem. Soc., Chem. Commun. 1973, 636) by J. A. Ellman for multidirectional cleavage from the resin (J. Am. Chem. Soc. 1994, 116, 11171)

1995:

Synthesis of a potent ACE inhibitor by combinatorial organic synthesis on solid support using a 1,3-dipolar cycloaddition reaction by M. Gallop et al. (WO 95/35278, 1995)

1995:

Use of a genetic algorithm for the selection of the products of an Ugi four component reaction (Angew. Chem. Int. Ed. Engl. 1995, 34, 2280)

1996:

Use of the Ugi four component reaction in combination with a 1,3-dipolar cycloaddition reaction of intermediary formed "Mtinchnones" with electron-poor acetylenes by R. Armstrong et al. (Tetrahedron Lett. 1996, 37, 1149)

1. Introduction, basic conceptsand strategies 1997:

Combination of a cyclo-condensation reaction, multicomponent diversification and multidirectional cleavage from the resin using a novel combined "safety-catch"- and traceless linker yielding highly diverse pyrimidines by D. Obrecht et al. (Chimia 1996,

11, 530; Helv. Chim. Acta 1997, 80, 65) and L. M. Gayo et al. (Tetrahedron Lett. 1997, 38, 211). 1997:

Synthesis of a taxoid-library using radiofrequency-encoding

(J. Org. Chem. 1997, 62, 6092)

Many recent reviews and books summarise the work that has been done in this field:

Functionalized resins and linkers for solid-phase synthesis of small molecules: C. Blackbum, F. Albericio, S. A. Kates, Drugs of the Future 1997, 22, 1007.

Functionalised polymers: Recent developments and new applications in synthetic organic chemistry: S. J. Shuttleworth, S. M. Allin, P. K. Sharma, Synthesis 1997, 1217. Recent developments in solid-phase organic synthesis: R. Brown, Contemporary Organic Synthesis 1997, 4, 216. Solid-Phase Organic Reactions H. A Review of the Recent Literature: P. H. H. Hermkens, H. C. J. Ottenheijm, D. C. Rees, Tetrahedron 1997, 53, 5643.

Organic synthesis on soluble polymer supports: Liquid phase methodologies: D. J. Gravert, K. D. Janda, Chem. Rev. 1997, 97, 489.

The current status of heterocyclic combinatorial libraries: A. Nefzi, J. M. Ostresh, R. A. Houghten, Chem. Rev. 1997, 97, 449.

Combinatorial Chemistry, Synthesis and Application. S. R. Wilson, A. W. Czarnik, Wiley (1997) Combinatorial organic synthesis using Parke-Davis' s DIVERSOMER | method: S. Hobbs DeWitt, A. W. Czarnik, Acc. Chem. Res. 1996, 29, 114.

1.2. Historicallandmarksin solid-supportedorganicsynthesis

Multiple-component condensation strategies for combinatorial library synthesis: R. W. Armstrong, A. P. Combs, P. A. Tempest, S. D. Brown, T. A. Keating, Acc. Chem. Res. 1996, 29, 123. Design, synthesis and evaluation of small-molecule libraries: J. A. Ellman, Acc. Chem. Res. 1996, 29, 132. Strategy and tactics in combinatorial organic synthesis. Applications to drug discovery: E. M. Gordon, M. A. Gallop, D. V. Patel, Acc. Chem. Res. 1996, 29, 144.

Synthesis and application of small molecule libraries: L. A. Thompson, J. A. Ellman, Chem. Rev. 1996, 96, 555.

Solid-phase organic reactions: a review of the recent literature: P. H. H. Hermkens, H. C. J. Ottenheijm, D. Rees, Tetrahedron 1996, 52, 4527. Combinatorial synthesis of small-molecular-weight organic compounds: F. Balkenhohl, C. von dem Bussche-Hfinnefeld, A. Lansky, C. Zechel, Angew. Chem. 1996, 108, 2436.

Organic synthesis on solid phase: J. S. Friichtel, G. Jung, Angew. Chem. Int. Ed. Engl. 1996, 35, 17. Kombinatorische Synthese: K. Frobel, T. Kr~imer, Chemie in unserer Zeit 1996, 30, 270. Combinatorial Peptide and Nonpeptide Libraries. G. Jung (Ed.), VCH, Weinheim (1996) Combinatorial Libraries. Synthesis, Screening and Application Potential. R. Cortese (Ed.), W. de Gruyter, Berlin (1995). Applications of Combinatorial Technologies to Drug Discovery. 1. Background and Peptide Combinatorial Libraries. M. A. Gallop, R.W. Barret, W. J. Dower, S. P. A. Fodor, E. M. Gordon, J. Med. Chem. 1994, 37, 1233. Applications of Combinatorial Technologies to Drug Discovery. 2. Combinatorial Organic Synthesis, Library Screening Strategies, and Future Directions. E. M. Gordon, R. W. Barrett, W. J. Dower, S. P. Fodor, M. A. Gallop, J. Med. Chem. 1994, 37, 1385


1.3. Applications of solid-supported organic chemistry Although the combinatorial and parallel synthesis of compound libraries devoted to screening, lead finding and lead optimisation purposes have initiated a real burst of interest for solid-phase organic synthesis (SPOS), there are numerous other applications and opportunities for SPOS emerging from related areas. This chapter will summarise the fields of interest for SPOS and some of those will be discussed more extensively in the following chapters.

Development of novel soluble and insoluble polymer supports To date still most of the resins that are employed in SPOS are derived from polystyrene (for more details see Chapter 1.5). Although polystyrene has certainly many excellent properties there is currently a great interest in finding novel resins with modified mechanical and chemical properties, such as amphiphilic resins consisting of co-polymers of functionalised polystyrene- and polyacrylamide subunits.17,18 The aims of this field of research can be summarised as follows: 9 increase of the mechanical and chemical stability of the polymers 9 extension of the scope of reactions that can be performed on solid supports 9 amphiphilic resins that are compatible with aqueous reaction conditions 9 shorter and less extensive washing procedures 9 development of soluble dendrimeric polymers with high loading capacities which can be easily precipitated 9 development of novel anchors that are compatible with a broad range of reaction conditions and allow a high loading capacity 9 beneficial effects of high loaded resins on some reactions and on the resin cleavage procedures; drawbacks might be anticipated in intramolecular cyclisations

Use of solid-supported reagents (cf. Chapter 1.6) One crucial advantage of performing parallel and combinatorial chemistry in solution is the fact that most organic reactions have been studied and developed in solution. Thus, many reaction protocols can be directly applied in a parallel format without having to go through tedious reaction development procedures. On the other side, solid-supported strategies offer the benefit of easy automation and rapid isolation and purification procedures. Insoluble reagents might really constitute the future for solution strategies in that by-products resulting from the reagents can be removed by simple filtrations and thus offer all the benefits of solid-phase and solution chemistry. Many solid-supported reagents have been described in the literature or are commercially available (cf. Chapter 1.6) but their use has so far been limited to more academic studies. Novel reagents

10

1.3. Applications of solid-supported organic chemistry

grafted on highly loaded resins will certainly emerge as important tools in the field of parallel and combinatorial chemistry in solution. Some of the most important features of polymer-bound reagents are demonstrated schematically in Figure 1.3.1. Figure 1.3.1

The polymer-bound peracid described by Frdchet et al. 5 which was easily obtained by

H202

oxidation of the corresponding benzoic acid can be used to oxidise olefins to epoxides. The purification is achieved by simple filtration of the polymer-bound reagent, which can be recycled and re-used. It has to be pointed out, however, that after a few reaction cycles the reagent looses some of its initial activity. Nevertheless, this example demonstrates nicely the potential of polymerbound reagents in combinatorial organic synthesis (COS) (more examples will be presented in Chapter 1.6).

Supports for linear syntheses Solid phase chemistry originally started with Merrifield's pioneering polypeptide synthesis. 3 Due to the highly repetitive cycles of deblocking-, washing- and coupling procedures, peptide synthesis became a prime target for solid-phase synthesis. 2 For the last thirty years solid-phase peptide synthesis has matured to become a highly automated and powerful technology. Closely related to the linear assembly strategy of polypeptides, the synthesis of oligonucleotides2,16 and oligosaccharides 2,19 also initiated a lot of interest. The iterative nature of linear assembly strategies is schematically shown in Figure 1.3.2. After having grafted the first suitably protected building block (BB1) containing orthogonally protected functional groups G 1 and G 2 (amino acids for peptides, mono-nucleotides for oligonucleotides and mono-saccharides for oligosaccharides) with a suitable linker to the polymeric support, BB2 is coupled after cleavage of the blocking group (BG) followed by the usual washing procedures. This process is repeated n times, the protected functional groups G1-G2n+2are deprotected and the linear biopolymer is subsequently cleaved from the resin. 11


Figure 1.3.2

12


Following this protocol, it is quite understandable that polypetides, oligonucleotides and oligosaccharides, which belong to the three major classes of biopolymers, constituted the ideal platform for combinatorial chemistry. Extensive studies on the coupling procedures of the corresponding activated amino acid-, mononucleotide- and monosaccharide derivatives and a whole plethora of suitable protective groups and building blocks were available ready to start the combinatorial chemistry.

Traps for toxic and/or odorous molecules Functionalised polymers have been used to covalently or ionically extract unpleasantly smelling and / or toxic molecules from a solution. 2~ A classic example is given in Figure 1.3.3.

Figure 1.3.3

Natural oil containing or-methylene lactones as strong allergens were extracted with a polystyrene derived amino resin to yield the polymer-bound Michael-addition product which could be f'lltered off. It is interesting to note that the allergenic m-methylene lactones could be regenerated by sequential reaction with methyl iodide and NaHCO 3 liberating N,N-dimethylaminomethyl polystyrene. Following the same idea, notoriously unpleasantly smelling thiols can be captm'ed via disulfide bond formation with a polymer-bound thiol. Further examples will be shown in Chapter

1.6.

13


Support for unstable and explosive reagents It has been stated numerous times that polymer-bound reactive intermediates are more stable than the corresponding solubilised counterparts. The stabilisation forces exerted by the polymeric matrix are most probably due to hydrophobic clustering. Polymer-bound peracids are believed to be more stable and not explosive. 2,5 The hydrophobic nature of polystyrene resins in combination with the high dilution effect has been used successfully several times to accelerate intramolecular cyclisations by grafting molecules onto a solid support as shown in Chapter 1.6. 21,22

Immobilisation of synthetic receptor molecules Polymer supports have been used in order to covalently graft enzymes and receptors in order to perform biological tests (ELISA assays). Recently, polystyrene derived resins have been used to covalently link cationic and anionic 23 synthetic receptor molecules. A particularly nice example of a polystyrene-grafted phosphate binding synthetic receptor is shown in Figure 1.3.4. Figure 1.3.4

Polymer-supported macrocycles A and B are able to take up nucleotide phosphates such as adenosine di- and triphosphate (ADP and ATP) at pH 4

14


Combinatorial and parallel synthesis of small-molecular-weight compound libraries Among the many applications of solid supports that have emerged recently, the synthesis of compound libraries for biological screening purposes by combinatorial and parallel techniques has certainly created the largest interest. The possibility of creating families of hundreds and thousands of interesting molecules by combinatorial and parallel organic synthesis has attracted with equal intensity scientists from academic and industrial organisations, especially those institutions dealing with biological screening such as pharmaceutical and agrochemical companies. A library of compounds is defined as an ensemble or a family of compounds that have originated from the same assembly strategy and building blocks. Thus, the members of a library exhibit a common core structure with differing appended substituents. As shown in Chapter 1.8 the library can consist of single compounds or mixtures depending on whether a parallel or "split-mixed" synthesis strategy was used. The idea of generating ensembles or families of molecules by synthesising all possible combinations of building blocks of type A, B and C in parallel or combinatorial fashion was certainly attractive to many scientists. This account focuses on the solidsupported synthesis of small-molecular-weight compound libraries and we will try to explain the chemical strategies including solid supports, linkers, reactions and reactive building blocks that are especially useful for combinatorial and parallel synthesis. In Figure 1.3.5 we consider for the sake of simplicity the different combinations of building blocks A 1-3, B 1-3 and

C 1-3 that

are possible.

As can be schematically seen in Figure 1.3.5 the number of resulting products depends highly upon the nature of the reactive building blocks and the assembly strategy. In chart a) where A=B=C (=A 13, e.g. amino acids), 27 linear tripeptides with the same basic core structure are the result of all permutations of three amino acid building blocks. In chart b) where building blocks A, B and C are of different nature but can be assembled only in one linear fashion again 27 products with the same basic core structure can be obtained. Conversely, in case c) where again A, B and C are different but can be assembled in all six possible linear ways 162 products with six different basic core structures can be obtained. In chart c) where it is assumed that A, B and C are assembled in a cyclic arrangement with only one directional assembly possible, 27 cyclic products can be obtained which are cyclic analogues of the products obtained in chart b). For the case where all cyclic directed permutations are possible we can obtain 54 cyclic products with two different core structures. This in fact only one third of the linear analogues described in chart c). This simple sketch shows that the type and the permutability of building blocks A, B and C and the assembly strategy play an equally important role in determining the number and the nature of the compounds that can be obtained. It is striking to note that the permutability of building blocks A, B and C (compare Figure 1.3.5 charts b) and c)) not only increases the number of final compounds from 27 to 162 but maybe even more importantly increases the number of core 15


structures from one to six. While introducing cyclic core structures the number of products diminishes from 162 to 54 (compare Figure 1.3.5 charts d) and e)). This reduction in numbers is compensated by the fact that the cyclic compounds are more rigid and the diversity is spatially more condensed. Figure 1.3.5 A = B = C (e.g. amino acid building blocks)" { 33 = 27 tripeptides I (=A13)

one core structure

A ~ B 4=C: only one linear assembly possible" 3x3x3

A~B---)C

27 combinations ofA-B-C I

one core structure c)

A ~ B 4=C:

six linear permutations possible"

3x3x3x6

A ~ B---) C A~C--)B B ~ A---) C B ---) C ~ A C--~A~B

162products

C~B~A

six linear core structures d)

A4:B~C

only one directed sequence possible "11.

I 3 x 3 x 3 = 27 cyclic products ] one core structure e)

A~=Br

all cyclic permutations possible 2 x 3 x 3 x 3 = 54 cyclic products ] two core structures

In Chapter 1.8 we will present extensively the synthetic strategies used in parallel and combinatorial chemistry and in Chapter 1.9 we will present a classification of the reactive building blocks of type A, B and C according to their reactivity. In addition to discussing the pivotal role of reactive building blocks and their permutability ("combinatorics of reactive building blocks") we will focus on the important role of solid-phase chemistry for the synthesis of small-molecularweight compound libraries including linker strategies, synthesis and resin cleavages.

16

1.4. The role of solid-supported chemistry in modern drug discovery

1.4. The role of solid-supported chemistry in modern drug discovery 1.4.1. The four key elements of lead finding The smooth interaction of four key elements has been determined as being crucial for a successful and fast drug development process as schematically shown in Figure 1.4.1.

Figure 1.4.1

New targets: -Due to the enormous progress made in genomic sciences, molecular biology and biochemistry, an ever-growing number of biologically important target proteins (e.g. receptors, enzymes, transcription factors, modulators, chaperones) have become available in pure form allowing to study their structure, function and biological role in riving systems. Several crystal structures of pharmacologically relevant proteins (e.g. platelet derived growth factor (PDGF), 24,25 nerve growth factor (NGF), 26 HIV-proteinase, 27 collagenase, 28 insulin receptor kinase domain,29, 30 calcineurin/FK BP12-FK 506 complex 31) have initiated several successful drug development programs. In addition, the rapid elucidation of the entire human genome is expected to further amplify the number of novel biological targets that will become available to drug discovery.

17


High Throughput Screening ( H T S ) : - T h e discovery of novel biological targets was paralleled by the development of novel assays and high throughput screening (HTS) technologies including miniaturised screening formats, allowing to test thousands of individual compounds per day. New molecules: -Since a successful clinical compound originates in average from the evaluation of a pool of 10'000 related analogues, the appearance of novel targets and high throughput screens called for novel sources of structurally and chemically diverse compound collections. Hence, chemists were challenged to develop high throughput synthesis techniques in order to satisfy the increasing demand for screening compounds and allow to maintain a reasonable rate for the detection of valuable hits and leads for subsequent lead optimisation.

Data management: - Integrated data management concepts had to be developed in order to handle the enormous wealth of data arising from chemical and biological data bases. While up to roughly 1980, drug dicovery was driven by random screening and the chemical and biological intuition of the scientists, the last fifteen years of drug discovery have been heavily influenced by the structural knowledge of the target protein and molecular modelling techniques which allowed in some cases to produce tailor-made ligands.32, 33 This so-called "rational drug design approach" was quite successful in finding potent ligands for well defined enzyme and receptor cavities. 32 Large surface spanning ligand-receptor interactions, however, have been a challenge for drug discovery programs34 and it has been notoriously difficult to find small molecules as lead compounds. 25 Amino acid derived peptide mimetics,35,36 corresponding to exposed protein epitopes such as 13-turns, loops, 310- and (x-helical structures, which can serve as valuable tools to probe potential ligand-receptor or ligand-enzyme interaction sites have found widespread applications in these structurally more demanding cases. Hence, integrated approaches combining structural knowledge from conformationally

constrained small peptides and

combinatorial and parallel synthesis of small molecules seem particularly well suited for this purpose. 37 This integrated approach combining rational and random elements is shown in Figure 1.4.2.

18


Figure 1.4.2

Target Identificationand Selection

(Enzymes, Receptors, Transcription Factors .... )

Protein Expression1 and Purification

1

1

Structure Determination / X-Ray, 2D- and 3D-NMR

'

~

I t~

G)

a

O

"0

It"

T ~ [ L,ean',;L'c~a~n~ i

I

Cocrystallisationof "11 Ligand and Target ProteinJ Structure Based I "De Novo" Design

tv

_ Lead/Ligand/ - Optimisation

Once a target protein has been identified and selected, it is expressed, amplified and purified using modem biochemical techniques. As soon as the protein is available in pure form and homogeneous form, and in sufficient quantities, the phases of structure determination and assay development

19


usually start simultaneously. Once a sensitive assay has been developed, it is transferred into a format suitable for HTS. Screening of compounds collections as single compounds or as mixtures can then be initiated. Depending on the performance of the test, the compound collections will be screened in a completely random fashion, or, conversely only a subset will be selected based on 2D- and 3D-clustering techniques 13 and screened. After an active ligand molecule has been identified it can serve as a starting point for a lead optimisation program. Alternatively, in the case where crystals suitable for X-ray crystallography are available, the ligand molecule can be cocrystallised and the resulting structural information used for structure-based "de novo" design to find more potent ligands. In the ideal case the rational and random approaches converge into lead compounds showing common structural features which will be ultimately transferable into a development compound.

1.4.2. Sources for novel lead compounds The different sources for novel lead compounds are schematically represented in Figure 1.4.3.

Natural products: 9 structurally highly diverse 9 molecular weight -400-1000 9 often biologically active ("biological activity maximised through evolution") 9 optimisation process is time-consuming 9 high manufacturing costs Natural products isolated from plants, microbes, and animals of terrestrial and marine origin have a long-lasting tradition in medicine. 38 Nature's architecture offers a virtually unlimited plethora of diverse chemical scaffolds going beyond human imagination and hence natural products represent the structurally and chemically most diverse source for finding new lead compounds. Taxol, 7 monensin, 39 avermectin, 4~ mitomycin41-43 and FK50644 are only a few examples of natural products that served as starting points for intense optimisation programs. Although this process of lead optimisation is usually very time-consuming and manufacturing costs of the final drugs are high, it is expected that natural products will rather gain importance in lead finding.

20


Figure 1.4.3

RationalDesign

RandomDesign

# 03 t..

E

.Q

t--

o'J

~Peptoids, Peptides,~ Peptidomimeticsderivedfrom) ~...~a rget Protei.~.//

== .== ..J

Eo

High 1 Throughput Screening

N 03

E

l

"1o

g

AnalysiSLead and1 Identification

G) L_ t~

L_ JQ .m ..J 10

D 0 0

Lead I Optimisation

L_

_J 10

_~=

Development Compounds1

0

o

21


Synthetic compounds collections9 molecular weight ,-300-550 9 "drug-like" 9 structural diversity is limited 9 optimisation process straightforward 9 low manufacturing costs A highly useful source for finding novel lead compounds constitute the compound collections of synthetic small-molecular-weight compounds that have been accumulated over the past decades in industrial companies and academic institutions. Since these compound collections are usually derived from a limited amount of so-called "priviledged" core structures such as benzodiazepines, dihydropyrimidines, phenothiazines and others, they exhibit a more limited chemical and structural diversity than natural products. Due to their ususally simpler structure a given hit or lead can be subsequently optin~sed in a quite efficient manner resulting in low manufacturing and development costs.

Peptoids, peptides and peptidomimetics derived from a target protein9 fast assembly through linear assembly of similar building blocks 9 limited, "rather flexible" diversity 9 molecular weight > 600 9 usually not"drug-like" 9 optimisation process often long and tedious As indicated previously, many pharmacologically interesting target receptors exhibit large surface spanning areas where it has been notoriously difficult to find small molecules as inhibitors. For this purpose peptoids, peptides and especially peptidomimetics derived from structural information of the targets can be valuable tools for lead finding (cf. Chapter 2).

22


Small-molecular-weight chemistry:

compound

libraries

from combinatorial

and

parallel

9 fast and convergent assembly using reactive building blocks 9 limited chemical and structural diversity 9 "drug-like" 9 molecular weight < 600 9 fast optimisation phase 9 low manufactoring costs These libraries are excellent tools to complement the compound collections already available in terms of numbers and diversity. Hits and leads that have emerged from such a library are especially valuable since the optimisation process is speeded up by the usually fast and convergent assembly strategies that were used to synthesise the compounds. The structural complexity of the resulting compounds is only limited by the chemical strategies that are possible, the reactive building blocks that can be employed and by the number of available building blocks that can be engaged for the final derivatisation of a given library. As shown in Figure 1.4.3 the compound collections will be rather large and of random type in the early phases of hit and lead identification. Based on the first lead structures emerging from HTS, more tailor-made compound collections will be synthesised or selected from existing compound libraries. Rational design elements at that stage will help to reduce the size of the compound collections that will be synthesised or selected for further screening. Lead compounds generated by combinatorial and parallel chemistry are of particular value at that stage of development as the optimisation process is accelerated by the modular synthetic approaches used by these techniques. In the lead optimisation phase, focused libraries of reduced size, containing all the structural elements of a given lead compound can have a significant input on a faster development of clinical candidates. In addition, several structural analogues can be followed simultaneously which should result in faster development times and thus effectively help to reduce the overall development costs.

23


1.5. Solid supports As indicated in Chapter 1.3, polymeric supports have been mainly used to immobilise substrates, reagents and catalysts. Insoluble polymeric matrices allow to fully exploite the ease of solid-liquid separation by filtration. In addition, certain soluble polymers were examined which can be easily precipitated. The polymers which were used for the synthesis of small organic molecules can be divided in the following classes:

-Crosslinked organic polymers:

-insoluble in organic solvents -microporous polymers, gels (e.g. polystyrene, poly-(4-vinylpyridine)) -macroporous polymers (e.g. polystyrene derived beads)

-Linear organic polymers:

-usually soluble in organic solvents and can be precipitated in certain cases (e.g. polyethylene glycol (PEG), polystyrene)

-Dendrimers: -Inorganic supports"

-solubility depends on size and shape -porous glass -SiO 2 -A1203 -clays -graphite

1.5.1. Immobilisation of substrates The synthesis of oligomeric molecules such as polypetides, oligonucleotides and oligosaccharides and small molecules have generally been performed either by using soluble linear, usually PEGpolystyrene-derived supports, 47-50 whereby the isolation and purification of the polymerbound substrates occurs by precipitation,45,46,48,49 ultrafiltration, 51 dialysis or gelfiltration. 47 This

45,46 or

technology takes formally advantage of combining benefits of well established solution chemistry with simple purification procedures. These purification procedures, however, are often tedious to perform and not generally applicable for automated synthesis.

24

1.5. Solid supports

The vast majority of applications in the field of solid-supported synthesis, however, use insoluble polymeric matrices. The advantages of using insoluble polymers can be summarised as follows: 9 purification can be performed by simple washing andfiltration cycles 9 allows the use of large excesses of reagents (typically 3-5 equivalents) 9 high concentrations of reagents allow slow reactions to be driven to completion 9 reaction-, washing- andfiltration steps can be easily automated

Among the polymeric supports that have been employed in solid phase synthesis we mostly find polystyrene derived resins crosslinked with varying amounts of divinylbenzene (DVB, typically 15%). These resins consist mainly of spherical beads of various sizes. Depending on the polymerisation protocol these resins can be of the micro- or macroporous type. The resins having found wide applications in organic synthesis are listed below: 9 Micro-

and

macroporous

polystyrene

/

DVB-crosslinked

resin

beads

(Merrifield-type resins). These resins are fairly cheap, can be easily functionalised with high

loading (typically 1-3.5 mmol/g) and are extensively used in solid-supported polypetide- as well as in small molecule synthesis. 9 P o ly s t y ren e glycol

/ DVB-crosslinked

polymeric

spacers of various sizes (e.g. TentaGel|

matrix coated with p o l y e t h y l e n e -

These resins are less hydrophobic

and show better swelling properties in aqueous solutions. They are usually mechanically less stable, more expensive and show a lower degree of loading than the Merrifield-type resins. They find extensive use in solid-supported polypetide and small molecule synthesis. 9 Tea Bags: 9 polystyrene/DVB-derived resin beads sealed in a porous polypropylene bag developed originally by Houghten et al. Each bag contains one type of labeled polymerbound molecule. Different tea bags can be mixed and are allowed to react with the same building block, can be washed in parallel and then be separated. Since the reactions take place in separate reaction compartments there will be only one type of well specified molecule in each bag. This protocol also allows the synthesis of larger quantities of material. Similar to the "split-mixed" technology the number of coupling steps is reduced while all the benefits of solid-supported chemistry are maintained. This methodology has been mainly used for the combinatorial and parallel synthesis of polypeptide libraries. 9 Diversomer|

53-56 Parallel solid-phase synthesis of individual compounds

('diversomers') is achieved in spatially separated compartments using an apparatus allowing

25

1. Introduction, basic conceptsand strategies the simultaneous handling of an array of resin-bound intermediates. During synthesis the resin is located in glass tubes equipped with frittes at their lower ends, dipping in the wells of a reservoir block containing solutions of reagents. 9 Pins: 57 polystyrene-or polymethacrylamide-dimethylacrylamide-(copolymerised) derived matrices grafted on polyethylen crowns which are attached on top of pins. The pins usually are assembled in the typical 96-well plate format. This technology originally developed by

Geysen et al. 8,57,58 for the parallel synthesis of polypetide libraries has found wide applications also for the synthesis of small-molecular-weight compound collections 59-62 9 Other supports such as foils 63 and cellulose disks 64 should also be mentioned.

1.5.2. Immobilisation of reagents and catalysts

Polymer-bound reagents and catalysts which can be used in large excesses are ideally suited to achieve the complete conversions of reactions in solution. In addition, this approach offers the attractive feature that well established solution protocols can be used while maintaining the easy purification procedures associated with insoluble polymers. This should ultimately result in shorter development times. Many polymer-bound reagents and catalysts, although commercially available (cf. Chapter 1.6), show several drawbacks such as low loadings and varying qualities which result in unreproducible yields. The relatively high prices might account for the fact that these polymerbound reagents and catalysts have not yet found wide applications. As mentioned in Chapter 1.3, many research groups have focused on the development of cheap, recyclable and highly loaded reagents and catalysts suitable for the synthesis of small-molecular-weight compound libraries in solution. The following polymeric matrices have been extensively used to graft reagents and catalysts: 9 Inorganic

polymers: 65,66 SiO 2, silicates, A1203, charcoal, molecular sieves, porous

glass. 9 Organic p o l y m e r s : 2,66,67 polystyrene crosslinked with DVB and poly-(4-vinylpyridine) crosslinked with DVB.

26

1.5. Solid supports

1.5.3. Crosslinked polystyrene-derived matrices Crosslinked polystyrene beads are obtained by free radical initiated copolymerisation of styrene and varying amounts of divinylbenzene (DVB). A suspension of water, styrene and DVB is mixed in the presence of a free radical catalyst such as dibenzoyl peroxide or azoisobutyroniu'il (AIBN) and heated to the reaction temperature suitable for polymerisation. The aqueous phase initiates a f'me dispersion of the mixture of monomers and serves as medium to control the reaction temperatm'e but does not participate in the reaction. Coalescence of monomer droplets leads to association and the formation of droplet conglomerates and larger monomer units by means of fusion of monomers. Efficient mechanical stirring of the reaction mixture results in the formation of a dynamic equilibrium but is not sufficient to suppress the aggregation of viscous droplets during the polymerisation process. Suspension stabilisers such as polyvinylalcohol or derivatives of cellulose are added in order to avoid these aggregations and to ensure a successful and reproducible polymerisation. These aggregation phenomena can also be suppressed by addition of salts to the aqueous phase which results in a change of the surface interface forces. Thus the polymerisation proceeds in each droplet and initiates the formation of a polymer bead whereby the bead size can be controlled by the stirring speed, the relative amounts of aqueous and monomer phases, the amount and nature of the suspension stabilisers (dispergator) and by the reaction temperature. The size of the beads can also be controlled by means of sieving. The swelling properties of the resin beads depend in essence from the degree of crosslinking and thus from the relative amount of DVB to the core monomer. 68-70 Resins containing a low degree of crosslinking (typically 1-2% DVB) show a more pronounced swelling capacity than those with a high content of DVB 71 (> 5%). The size and the shape of the resin particles can be directed to a certain extent by suspension polymerisation.

Microporous resins.- These resins, also called gels or temporary porous resins, show a low degree of crosslinking 72 (DVB content of 1-2%) and high swelling properties (see Table 1.5.3.1). The swelling properties depend also on the nature of the attached functional groups, e.g. chloromethyl polystyrene (crosslinked with 1% DVB) swells four times as much in chloroform as 4-nitro-chloromethyl polystyrene whereas in DMF both resins show the same amount of swelling. 73 The solvent molecules form pores which collapse when the resins are dried.

27


Table 1.5.3.1. Swelling properties of polymers in different solvents swelling capacitya)

solvent

crosslinked PS (1% DVB) b) MeOH

0.95

EtOH

1.05

Merrifield resin (2% DVB) c)

MeCN

1.0 1.0

AcOH 2.0

pyridine

3.0

DMF

3.5

THF

5.5

dioxane

4.9

EtzO

2.6

CHzC1 z

5.2

toluene

5.3

2.0

2.5

2.8

a) swelling capacity = volume of the swollenresin / original volume b) values according to Ref.74 c) values according to Ref.75 The synthesised resin beads show inhomogeneous crosslinking density which can be explained by the fact that DVB is more reactive towards polymerisation than styrene. 72

Macroporous resins.- These resins, also called macroreticular or permanently porous resins, can be obtained when the polymerisation process is conducted in the presence of an inert solvent72, 76 ("porogen"). Whether a macroporous or microporous resin is obtained depends largely on the ratio of the content of solubilising and crosslinking agents. Absence or low contents of porogen and low degree of DVB usually yield microporous resins whereas high content of porogen (e.g. toluene) and high degree of DVB rather lead to macroporous polymers. Alternatively, macroporous resins are also formed by using a high content of DVB in the presence of a non-solubilising agent such as 2-ethyl capronic acid. 72 Agglomerates of small and smallest resin particles (termed microspheres or nodules) which depending on their DVB content can significantly swell, form macroreticular beads which keep their porous character in the dried state and show a large pore surface (inner surface). 76,77 The pore surface and the pore size depend again on the reaction conditions and on the nature of the porogen. The functional groups in a microporous resin are homogeneously distributed in the whole bead. Their somewhat restricted solvent accessibility can be modulated by a solvent showing a high degree of swelling. Conversely, the functional groups of macroreticular resins are largely positioned at the outer surface of the bead. Thus, the reactivity and solvent accessibility of the functional groups does not 28

1.5. Solid supports

depend on the nature of the solvent and the swelling properties. 71 In this respect macroreticular resins can be compared with inorganic matrices. 66

1.5.4. Functionalised polystyrene resins The widespread applications of polystyrene derived resins is due to the fact that styrene consists of a chemically inert alkyl backbone carrying chemically reactive aryl side chains that can be easily modified. As discussed earlier, a wide range of different types of polystyrene resins exhibiting various different physical properties can be easily generated by modification of the crosslinking degree. In addition, many styrene derived monomers are commercially available and fairly cheap. Polystyrene is chemically stable to many reaction conditions while the benzene moiety, however, can be funtionalised in many ways by electrophilic aromatic substitutions or lithiations. As shown in Scheme

1.5.4.1

there are principally two different ways to

obtain

functionalised

polystyrene/DVB-copolymers. Scheme 1.5.4.1 t t

s

FG w

B 4-

+

FG Approach A consists of building first the polystyrene/DVB-copolymer followed by subsequent chemical introduction of the functional group, whereas in approach B the functional group is already introduced in a modified styrene-derived monomer. The chemical modification of crosslinked polystyrene (approach A) offers the advantage that only the accessible aromatic tings and positions on the aromatic rings are functionalised. The drawback of this approach is that the reactions on the polymer are usually slower and difficult to monitor which can significantly affect the yields due to side reactions and thus the degree of loading. Approach B assures the exact positioning of the functional groups and usually a high degree of loading but necessitates the synthesis of the appropriate monomers. Since the first functionalisation determines the loading of the resin it is important that these reactions proceed in high yield and with high fidelity.

29


1.5.4.1.

Chloromethylated p o l y s t y r e n e s

Chloromethyl polystyrene was introduced by Merrifield 3 into peptide synthesis. It was used, however, first as an intermediate for the synthesis of anion exchange resins. 78 The synthesis of chloromethylated polystyrenes is best achieved by Friedel-Crafts alkylation of polystyrene with methoxymethylene chloride in the presence of a Lewis acid catalyst such as SNC143,78 as shown in Scheme 1.5.4.2. Scheme 1.5.4.2

0'

0./

/

/

/ interstrand crosslinking

Reagents and conditions: i) CICH2OCH3, SnCI4, reflux, 1h ; CICH2OCH3, CHCI3, SnCI4,0~ 30 min;

CICH2OCH3, ZnCI2, THF, CH2CI2;CICH2OCH3, BF3OEt2, hexane, 35~ 3h. Investigations about the swelling properties of chloromethylated polystyrenes showed that up to a chlorine content of 19% (about 0.75 chlorine atoms per aromatic ring*) there was no significant drop in swelling. An increase of loading, however, led to a markedly less swelling resin indicating a higher degree of crosslinking by 'interstrand' couplings (Scheme 1.5.4.2). It could be shown by NMR-measurements that the ratio of para- to ortho-chloromethylation of soluble polystyrene was 95:5. 80 The same ratio can be expected for resins with a low degree of crosslinking. The use of ZnC12 instead of SnC14 for the chloromethylation with methoxymethylene chloride lead to a resin with a low degree of functionalisation. 81 Sparrow 82 was able to show that by using BF3OEt 2 as catalyst and ethoxymethylene chloride as alkylating agent the degree of loading could be controlled depending on the amount of catalyst. Chloromethylated resins were also synthesised by copolymerisation of styrene, divinylbenzene and chloromethylstyrene 17,83,84 (usually as a 3:2-mixture of meta and para isomers). Arshadi et al. 17 noticed, however, that this approach can lead to substantial losses of chlorine content.

* For calculationsof loadings and interconversionof different indicationssee Ref.79 30

1.5. Solid supports

Scheme 1.5.4.3

Reagents and conditions: i) BCI3, CCI4, 0~ 2h; ii) NaOCI, CHCI3

(or ClCH2CH2Cl), BnNEta+Cl-;SOaCla, benzene, AIBN, 60~ Merrifield resins with a chlorine content up to 22% (corresponding to 1.0 chlorine per aromatic

ring) could be obtained by copolymerisation of 4-methoxymethylstyrene with styrene and DVB and subsequent conversion using BC13 in CC1417 as depicted in Scheme 1.5.4.3. Chlorination of 4-methylpolystyrene (obtained by copolymerisation of styrene, DVB and 4-methylstyrene) with NaOC1 in the presence of a phase transfer catalyst 85 proved a valuable method for the preparation of

microporous

(1%

DVB-crosslinking)

and

macroporous

(20%

DVB-crosslinking)

chloromethylpolystyrene. This method was compared with a free radical chlorination using SO2C12 and AIBN as shown in Scheme 1.5.4.3. Using NMR-techniques it could be shown again that for a loading degree higher than 2.5 mmol/g also dichloromethyl groups were present. 85 Since the elemental combustion analysis gave higher chlorine contents than determined by NMR it was concluded that in both methods also partial chlorination of the backbone occurred. Guyot 72 investigated in some detail the advantages of the copolymerisation procedures and

concluded that a homogenous distribution of the functional groups was only achieved when the monomers showed a comparable reactivity. Some functional groups are usually buried in the interior of the polymer and will not be accessible by the solvents and the reactants. This drawback can be partially overcome by delayed addition of the functionalised monomer. 72 Hence, the maximum loading can be controlled by the amount of the functionalised monomer that is employed in a given polymerisation.

31


1.5.4.2. Aminomethylated p o l y s t y r e n e

resins

Aminomethylated, crosslinked polystyrenes constitute very valuable and versatile resins for a variety of applications. The amino group can be easily acylated for the introduction of spacer and linker molecules 86-90 and it was also used for the synthesis of polymer-bound carbodiimides. 91-93 In Scheme 1.5.4.4, some of the most common synthetic accesses to aminomethylated polystyrenes are summarised. Scheme 1.5.4.4

Reagents and conditions: i) NH3, CH2CI2; ii) potassium phthalimide, DMF; iii) N-(hydroxymethyl)- or N-

(chloromethyl) phthalimide, CH2CI2, TFA, catalyst (HF, CF3SO3H, SnCI4, FeCI3); iv) N-(hydroxymethyl)trifluoracetamide; v) NH2NH2H20, EtOH; vi) KOH, EtOH These methods comprise the conversion of chloromethylated polystyrene with non-aqueous ammonia described by Rich et al. 73 (Scheme 1.5.4.4, i)) which is quite slow. Excellent conversions are obtained by using potassium phthalimide 88,89,91-93 followed by treatment with hydrazine (Scheme 1.5.4.4, ii) and v)). The same phthalimido intermediate can be obtained by a Tscherniak-Einhorn reaction 94 using N-(hydroxymethyl)- or N-(chloromethyl)phthalimide in the

presence of an acid catalyst such as HF, CF3SO3H or SnCl4 .86,87 The degree of functionalisation (typically 0.05 - 3.6 mmol N/g) can be controlled by the amount of reagent and the concentration of the catalyst as recently described by Zikos et al. 95 by using N-(chloromethyl) phthalimide in CH2C12 and FeC13 as catalyst. Loadings as high as 7.3 mmol N/g can be achieved but those resins show restricted swelling properties. Finally, aminomethylated polystyrene resins have also been

32

1.5. Solid supports

obtained via reaction with N-(hydroxymethyl)trifluoracetamide and subsequent saponification with KOH in EtOH. 87

1.5.4.3. Various functionalised polystyrene

resins

Besides aminomethyl polystyrene, many other functionalised polystyrene resins were prepared from chloromethyl resin by nucleophilic displacement (Scheme 1.5.4.5) Scheme 1.5.4.5

Reagents and conditions: ~ 1 (1% DVB, 0.73 mmol CI/g), KOAc, DMA, 85~ mmol CI/g), KOAc, DMA, 85~

24h 96 or 1 (1% DVB, 3.9

24h; 21 ii) LiAIH4, Et20, r.t., 4h or NH2NH2, DMF, r.t., 76h 96 or NH2NH2, DMF,

r.t., 20h; 21 iii) 1 (2% DVB, 2.8 mmol CI/g), KOH, 1-pentanol, reflux, 24h; 97 iv) 1 (1% DVB, 3.5 mmol CI/g),

33


thiourea, dioxane/EtOH (4:1), 85~

15h;98 v) KOH, EtOH/dioxane; vi) 1 (1% DVB, 1.15 mmol CI/g),

KSAc, DMF;99 vii) LiBH4, Et20, r.t.;99 viii) 1 (2% DVB, 1.36 mmol CI/g), NaCN, DMF, H20, 120~ 20h;75 ix) H2SO4, AcOH, H20, 120~ 10h;75 x) SOCI2, toluene, 110~ 24h;75 xi) 1 (2% DVB, 1.05 mmol/g), DMSO, NaHCO3, 155~ 6h; 1~176176 xii) 1,2-dimethoxyethane, m-CPBA, 55~

19h;100 xiii) 1 (2% DVB, 6.7 mmol

CI/g), CIPPh2, Li, THF. 102

The synthesis of various functionalised polymers containing spacer or linker units usually starts with a Friedel-Crafis alkylation of the basic polystyrene resin as depicted in Scheme 1.5.4.6. Treatment of polystyrene with propyleneoxide in the presence of SnC14 yields a resin containing a non-benzylic hydroxy group (Scheme 1.5.4,6). Prior to the addition of the reagent the resin is treated with the Lewis acid catalyst SnCI 4 forming a complex. 103 Neckers et al. 104 indicate that such complexes are also observed with other Lewis acids such as A1C13. The alkylation procedure described by Tomoi eta/. 1~ using microporous polystyrene resins with o)-bromoalkenes in the presence of trifluoromethane sulfonic acid presumably proceeds without additional crosslinking reactions as shown in comparison with similar experiments with soluble polymers. Scheme 1.5.4.6

Reagents and conditions: i) PS (1% DVB, degree of functionalisation 1-2.4 mmol/g), propylenoxide,

SnCI4, CH2CI2, 0~ ii) PS (2% DVB, degree of functionalisation 0.6-1.8 mmol/g), CH2=CH(CH2)gBr, CF3SO3H, 1,2-dichloropropane, 50~

Friedel-Crafls acylation of micro -90,106,107 and macroporous 1~ polystyrene resins yielded

conveniently the corresponding benzophenone-derived resins as shown in Scheme 1.5.4.7. These functionalised resins could be successfully be converted into trityl-, 108 oxim-derived 106 or the photolabile o-nitrobenzhydryl-derived resins 107 which were quite extensively used in peptide and oligonucleotide chemistry. In addition, 2-bromo propionylchloride in the presence of A1C139~ or FEC1395 was similarly used in acylation reactions with polystyrene resins. The reactions were carried out in solvents like CH2C12, 1,2-dichloroethane or nitrobenzene.

34

1.5. Solid supports

Scheme 1.5.4.7

Strongly acidic cation-exchange resins were obtained by sulfonylation of polystyrene using H2SO 4 or CISO3 H109 as shown in Scheme 1.5.4.8. Scheme 1.5.4.8

Reagents and conditions: i) H2SO4 or CISO3H" ii) HNO3, 0~ - 15~ 100~

iii) 9 SnCI2 2 H20, DMF,

6 h; iv) a) Et3N, CS2, 0~ - r.t., 4h; b) CICO2Et, 0~ - r.t.

35


Nitration of polystyrene resins followed by reduction with SnC12 resulted in aniline formation which was further converted into the corresponding isothiocyanate. This polymer was used as an insoluble reagent for Edman-degradation. 11o As shown so far many functionalised resins were obtained by electrophilic aromatic substitution reactions. A very valuable route to other functionalised resins constitute lithiation reactions on polystyrenes as shown by Fr~chet and Farral1111 and depicted in Scheme 1.5.4.9. Scheme 1.5.4.9

Reagents and conditions: i) PS (1% DVB), Br2, TI(OAc)3 or FeCI3, CCI4, Br2, r.t., lh, reflux, 1.5h;

or Br2, BF3, nitromethane, r.t., 18h; ii) nBuLi, hexane, toluene or benzene, 60~ iii) nBuLi, cyclohexane, TMEDA, 65~

3h;

4.5h.

Lithiated polystyrene resins can be obtained either via convenient bromine-lithium exchange reaction using nBuLi starting from 4-bromo-substituted polystyrene 102,111-115 or by direct lithiation of polystyrene using nBuLi in cyclohexane in the presence of TMEDA 111,116. This method, however, yields a mixture of para- and meta isomers. The bromination of microporous resins in the presence of the Lewis-acid catalysts was carried out in the dark whereby the degree of functionalisation could conveniently be controlled by the amount of bromine used in the reaction. 111 Macroreticular resins were brominated using Br 2 and FEC1371 or stoichiometric amounts of thallium acetate as Lewis acid catalysts. 113,114 The bromine-lithium exchange reaction on macroreticular PS-resins using nBuLi in THF could be driven to completion by repetitive lithiation as described by Fr~chet. 111 The lithiation of highly loaded microporous resins, however, were successfully carried out in toluene or benzene. The direct lithiation reaction of microporous polystyrene-derived resins (2% DVB) using nBuLi in cyclohexane in the presence of TMEDA is much faster than that of macroreticular resins (20% DVB). 116 It is interesting to note that for this reaction THF and benzene are not the solvents of choice. Using cyclohexane as solvent allows the synthesis of resins with a low or medium degree

36

1.5. Solid supports

of loading (up to 2.0 mmol/g). Highly loaded resins have to be synthesised via the brominationlithiation route. In S c h e m e 1.5.4.10 are shown functionalised PS-resins which were derived from lithiated polystyrene. S c h e m e 1.5.4.10

Reagents and conditions: ~ CO2 (dry ice), THF, PS (1% DVB)111 or CO2 (gas), THF, PS (2% DVB) or macroreticular PS (Amberlite| AE-305) "116 ii) $8, THF, lh then LiAIH4, THF (reduction of S-S bond), PS (1% DVB);111 iii) B(OMe)3, THF, r.t., 20h, aq. HCI, dioxane, 60~ 90min., PS (1% DVB);111 iv) CIPPh2,

37


THF, r.t., 105min, PS (1% DVB);111 or CIPPh2, THF, r.t., 4h, PS (2% DVB)115 or CIPPh2, THF, r.t., 4h, 70~

24h, (20% DVB);115 v) dimethyldisulfide, THF, PS (1% DVB)111 or dimethyldisulfide, THF,

macroreticular resin Amberlite| XE-305); 114 vi) DMF, THF, r.t., 105min. then NH2OH x HCI, pyridine, 90~ 4h, PS (1% DVB); 111 vii) benzophenone, THF, r.t., 2h, PS (1% DVB)111 or benzophenone, THF, r.t., 20% AcCI in benzene, reflux, PS (2% DVB);116 viii) BrCH2CH2Br, benzene, r.t., 150min., PS (1% DVB); 111 ix)MgBr2 x Et20, THF then nBuSnCI3, r.t., 24h, macroreticular PS (Amberlite| XE-305); 113 x) CI2SiMe2, benzene, r.t., 45min., PS (1% DVB);111 xi) PhN=C=O, benzene, PS (1% DVB);111 xii) ethylene oxide, toluene, PS (2% DVB).112

1.5.5. Polyacrylamide resins The functional groups of microporous resins can only react when the polymers show a high degree of swelling, which depends largely on the nature of the functional group. In the course of a synthesis on a polymer support the swelling properties of the resin can change significantly. In the

Merrifield peptide synthesis the starting polystyrene derived resin is of highly hydrophobic nature and becomes more and more hydrophilic as the synthesis of the peptide evolves and the chain grows. Due to such phenomena certain peptide sequences are notoriously difficult to be synthesised on a standard Merrifield resin. In order to improve the synthesis of the decapeptide sequence 65-74 of the acylcarrier protein Sheppard et al. 117 altered the hydrophobic nature of the polystyrene polymer backbone by introducing a polyacrylamide polymer backbone which they felt is quite similar to a peptide. The first polyacrylamide resins were synthesised by copolymerisation of N,N-dimethylacrylamide 1 (basic monomer), ethylenebisacrylamide 2 (crosslinking agent) and N-acryloyl-N'-(tertbutoxycarbonyl-I]-alanyl)hexamethylene diamine 3 (functionalised monomer) 118 as shown in

Scheme 1.5.5.1. Scheme 1.5.5.1 O

O

I

H

1

2

O

O

H

3

38

H

O

'~L'N ~ C O 2 0 H 3

1

4

1.5. Solid supports

Monomer 3 essentially serves to functionalise the polyacrylamide polymer after liberation of the primary amino group of the []-alanine moiety. The hexamethylenediamine groups serve as spacers in order to spatially separate the reactive groups. Monomer 3 was later on replaced by acryloylsarcosin methylester 4 (Scheme 1.5.5.1), 18 which is chemically closer to the basic monomer, in order to achieve a homogenous distribution of the functional groups. The persulfate initiated copolymerisation of 1, 2 and 4 (performed in emulsion with 66% aqueous DMF, 1,2-dichloroethane and cellulose acetate/butyrate as emulgator) yields beads with a high

degree of swelling (in H20, DMF, MeOH, pyridine or CH2C12 ten times the original volume, in dioxane about five times). 18,117 The aminolysis of the ester groups using ethylendiamine gives access to a resin containing free primary amino groups. The polymerisation of polyacrylamide gels within the pores of Kieselguhr 119 or polyhipestructures (PS-DVB-copolymer with 90% pore volume) 120 allows the synthesis of composite resins, which due to their low compressability are well suited for continous flow reactors. The Kieselguhr and polyhipe matrices serve thereby as skeletons whereas the polyacrylamide gels determine the chemical and swelling properties of the reactive matrix.

1.5.6.

TentaGel |

resins

TentaGel | polymers, originally developed by Bayer and Rapp,52,74 consist of a polystyrene matrix covalently coated with polyethylene glycol (PEG) chains and have been developed primarily for solid-phase peptide synthesis similarly to the polyacrylamide resins. TentaGel | resins have become quite fashionable in the field of solid-supported synthesis of small molecules. 12'6~ The PEG chains are introduced by anionic polymerisation of ethylene oxide with hydroxylated crosslinked polystyrene beads (Scheme 1.5.6.1).

Scheme 1.5.6.1

Reagents and conditions: i) ethylene oxide; ii) propylene oxide, SnCI4, CH2CI2;

iii) ethylene oxide, KOH, dioxane, 110~

39


An alternative procedure uses the functionalisation of [3-hydroxy polystyrenes which avoids the grafting as acid-labile benzylether groups to the polymer backbone, lo3 TentaGels are composed up to 60-80% w/w of PEG units determining largely their physical properties. They show good swelling properties in protic and polar solvents such as water, methanol, CH2C1z, MeCN, THF or DMF whereas in apolar solvents such as ether they hardly swell at all. The high flexibility of the PEG chains can be observed in NMR studies.52,74 The reactive centers are located at the end of the PEG spacers and are therefore easily accessible. Solvatised TentaGel*'s are pressure resistant and can be used in batch-procedures as well as in continuous flow reactors. Loadings of commercially available TentaGel|

range between 0.15-0.3

mmol/g which is significantly lower than those of PS-resins.

1.5.7. Novel polymeric supports PEGA is a copolymerisate of bis-(2-acrylamidoprop-l-yl)-PEG1900 (1), 2-acrylamidoprop-1yl[2-aminoprop-l-yl]PEG300 (2) and N,N-dimethylacrylamide (3) as depicted in Scheme 1.5.7.1.121 Scheme 1.5.7.1

1

PEGA 2

I 3

PEGA can be produced by bulk-polymerisation followed by granulation of the polymerisate or conversely by suspension polymerisation resulting in the formation of suitable beads for synthesis. PEGA beads were successfully used in solid phase peptide synthesis of the 65-74 fragment of the acylcarrier protein using the continous flow technique. The amino acid coupling reactions generally proceeded faster than the corresponding couplings on polyacrylamide gels on Kieselguhr. 121 The PEGA beads show excellent swelling properties in non-protic solvents such as CH2C12 and DMF 40

1.5. Solid supports

as well as in protic solvents like alcohols, H20 and aqueous buffers. PEGA resins are also compatible with enzyme catalysed reactions and have been employed for the enzymatic synthesis of a glycopeptide using a 13-(1-4)-galactosyltransferase 122 as shown in Scheme 1.5.7.2.

Scheme 1.5.7.2

PEGA beads have been employed to study protein-ligand interactions e.g. by Meldal et al. 123 who generated a library of polymer-bound protease substrates, which were C-terminally linked to a fluorescence donor (2-aminobenzoic acid) and N-terminally fixed to a fluorescence acceptor (3nitrotyrosine). The beads were subjected to the endoprotease Subtilisin Carlsberg whereby after proteolytic cleavage the fluorescence donor remains on the solid support. Fluorescent beads were subjected to sequence analysis, which not only revealed the sequence of the cleaved fragment but also the cleavage site. The use of such beads as anchor for grafting and simultaneously test potentially interesting enzyme inhibitors was developed by coupling a fluorogenic protease substrate onto PEGA beads. 124 In a second reaction sequence a library of potential protease inhibitors was generated using the "portioning and mixing" strategy generating beads containing both a substrate and an inhibitor sequence. The beads were treated with Subtilisin Carlsberg resulting in fluorencent beads where proteolytic cleavage had occurred and non-fluorescent beads where cleavage was prevented. After

41


sequencing, resynthesis and testing the peptides in solution, an inhibitory activity of 3 l.tM was obtained. 124 Meldal

et

al. 125 presented recently two

novel PEG-crosslinked

resins

derived

from

polyoxyethylene polystyrene (POEPS) and polyethylene polyoxypropylene (POEPOP) lacking amide derived polymer backbones resulting in an increased chemical stability. POEPS was obtained by "bulk polymerisation" of monomers I and 2 as depicted in Scheme 1.5.7.3. S c h e m e 1.5.7.3

P

/34

1

peroxide 100 ~ 12 h

POEP$

2

0

0

OH 3

KOtBu

100 ~ 12 h

v

POEPOP

The POEPOP resins are obtained by anionic polymerisation of monomers 3 and 4. The loading capacity can be controlled by the corresponding ratio of the monomers. Both POEPS and POEPOP resins show excellent swelling properties in solvents such as dichloromethane, DMF and water. C L E A R resins: CLEAR stands for Cross-Linked Ethoxylate Acrylate Resin. These resins belong to a group of highly crosslinked resins with good swelling properties, which are either obtained from "bulk polymerisation" or by suspension polymerisation 126 of monomers 1-6 as shown in Figure 1 . 5 . 7. 1. CLEAR resins differ from the standard crosslinked polymers by the incorporation of

branched crosslinking agents such as 1 and 6. The amino groups present in monomers 2 and 3 constitute the attachment points for potential linker groups*. CLEAR resins show excellent * Su and Menger 127 recently described tetrastyryl methane and proposed to use this compound as branched

crosslinking agent to generate resins with novel properties. 42

1.5. Solid supports

swelling properties in protic and aprotic polar solvents such as DMF, TFA, H20 , MeOH, CH3CN , THF and CH2C12 whereas they swell gradually in more lipophilic solvents such as toluene, EtOAc and hexane. Figure 1.5.7.1

CH2(OCH2CH2)IOCOCH=CH2 CH3CH2+CH2(OCH2CH2)mOCOCH=CH2 CH2=CHCH2NH2 CH2(OCH2CH2)nOCOCH=CH2 2 O

3

4

CH2OCOC(CH3)=CH2 CH3CH2+CH2OCOC(CH3)=CH2 CH2OCOC(CH3)=CH2

O

5

1

2

3

Clear I

la)

1

Clear II

3

3.6

Clear HI

8

4.4

Clear IV

12

50

Clear V

13

50

4

5

6

loading [mmol NH2/g ] 0.26

7.0

0.3 3.0

0.3 3.0

0.17 0.13

a) Ratio of corresponding monomers employed in the polymerisation process; the relative rate of incorporation of the monomers does not correspond to the same ratio. The high mechanical stability of CLEAR resins allow their use in continous flow reactors as used in solid phase peptide synthesis. The retroacylcarrier protein sequence 74-65 was synthesised successfully in the batch mode on these resins and their properties were compared to resins like polystyrene, polyhipe, PEGA and TentaGel |

43


1.6. Solid-supported reagents 1.6.1. Introduction Solid-supported reagents have been the subject of various books and review articles published since 1970. 2,5,66,128-136 Organic polymers such as polystyrene or poly(4-vinylpyridine) as well as many inorganic solid materials such as silica, alumina, graphite, clay minerals, or zeolites were used for the support of reagents and catalysts. In this chapter we will confine our discussion to reagents and catalysts supported by organic polymers and focus - after some general remarks - on their use in combinatorial chemistry. Many applications of these reagents were presented in the literature over the last four decades but the importance of this work was only recently fully estimated in the context of combinatorial chemistry and parallel synthesis. Besides their most obvious use in transforming low molecularweight substrates into products (for examples cf. Tables 1.6.1-1.6.10), they were applied as protective groups (e.g. monoprotection of symmetrically difunctionalised compounds 4) or used to promote intramolecular reactions (e.g. macrocyclisations, see below). Polymer-bound analogues of toxic, explosive, or odorous reagents (cf. Ref. 131 for leading reference) are safer and more convenient to handle as the corresponding soluble compounds. Furthermore, polymeric reagents were applied for mechanistic studies, 137-139as phase transfer catalysts (see 'triphase catalysis' 14o) and have been used in purification procedures involving the selective removal of products or contaminants from a solution. Advantages and disadvantages of supported reagents as compared to their conventional analogues have been discussed by several authors. 66,128,131 The easy separation of consumed reagent by filtration, allowing the use of excess reagent in order to obtain complete conversion of soluble substrates without laborious purification is considered a major advantage compared to soluble reagents. The primary disadvantage of supported reagents constitute their higher costs resulting from additional synthetic steps required for their preparation. This drawback may be partially compensated if a particular reagent is recyclable. Reagents (and catalysts) supported by organic polymers can be classified into two groups: The first group consists of reagents with functional groups covalently attached to the polymeric matrix. Such functionalised polymers are obtained either by chemical modification of the basic polymer or by copolymerisation of functionalised monomers with the basic monomers and a crosslinking agents as outlined in the previous chapter. Functionalised divinylsubstituted monomers 141,142 or dendritic monomers with attached functional groups 143 were also applied as crosslinking agents.

44

1.6. Sofid-supportedreagents

The second group consists of reagents supported by ion exchange resins. Amberlyst| resins are often used to support anionic nucleophiles, oxidants or reducing agents. Many of these ion exchange resins are commercially available or easily prepared from the chloride form (Scheme

1.6.1). Scheme 1.6.1

Reagents and conditions: i) NaOH; ii) X-

In general, the analysis of polymeric species is rather difficult and therefore, their exact structure is not always known. Polymeric trityl lithium 144 for example was prepared by reacting polystyrene with benzhydryl chloride in a Friedel-Crafts alkylation, affording polymeric triphenyl methane 1, which was subsequently deprotonated producing polymer 2 (Scheme 1.6.2).

Benzhydryl

substitution probably also occurs on the initially generated trityl groups, resulting in grafting of the polystyrene. 144 The polymer may therefore possess functional groups in different environments, with different accessibilities.

Scheme 1.6.2

Reagents and conditions: i) benzhydrol or benzhydryl chloride, AICI3, nitrobenzene; ii) BuLi, THF

Chemical transformations of polymers always include the possibility of undesired modifications which are difficult to recognise but might be responsible for low yields or purity of products if such polymers are used as reagents. Examples of intrapolymer reactions leading to additional crosslinking have been discussed in the previous chapter.

45


The reactivity of functionalised crosslinked polymers may significantly differ from that of analogous soluble reagents. Polymer-bound benzyne, generated by Pb(OAc)4-oxidation of resinbound 1-aminobenzotriazole 3, for example was converted into aryl acetates 4. This reaction was not observed if an analogous 1-aminobenzotriazole derivative 6 was oxidised in solution, where the formation of dimers (7 and 8) was predominant 145 (Scheme 1.6.3).

Scheme 1.6.3

Bz0

NH2 N

~ ~ ~A ~~ , ~ ".

i)

~ 0 B z

7

O

+

6

B

z

O

~

O

B

z

Reagents and conditions: i) Pb(OAc)4 ii) MeMgBr

Immobilisation prevents the benzyne intermediates from dimerisation and allows the altemative transformation which in solution is too slow to compete with dimerisation. Applications of functionalised

polymers

for

monoprotection

(many

examples

were

contributed

by

Leznoff, 4,116,146-150 further examples see Refs. 151,152) or monoactivation of symmetrically difunctionalised molecules as well as their use to promote the formation of large rings are based on this site isolation or "pseudodilution effect". 145

46

1.6. Sofid-supported reagents

Crosby et al. 114 investigated the monooxidation of heptanediol 10 using macroreticular poly(4-

methylmercaptostyrene) 9 and chlorine (Scheme 1.6.4). The product distribution was found to depend on the substitution degree of the polymer. Higher degree of functionalisation afforded increasing conversion of diol 10 but went along with increasing formation of dialdehyde 12 resulting from intrapolymer reaction. Scheme 1.6.4

Reagents and conditions: i) CI2, CH2CI2; ii) HO(CH2)7OH (10); iii) NEt3

Loading (mmol/g)

Product distribution 11

12

starting material 10

0.66

50.2 %

2.2 %

47.6 %

1.13

46.8 %

7.5 %

45.7 %

3.56

44.3 %

40.3 %

15.4 %

Appart from the degree of polymer loading, many other factors such as distribution of the functional groups in the polymeric matrix, conformational flexibility of the macromolecule, which depends largely on the degree of crosslinking, or the reaction rate determine the degree of site isolation. Apparent site isolation may result from kinetic factors if dissolved and attached substrate molecules compete for the remaining reactive groups of a polymer. Intramolecular formation of large rings can be carried out efficiently on solid support, which may help to suppress competitive intermolecular reactions, as illustrated by some recent examples: Macrocyclisation of the acrylamido peptide-3-iodobenzylamide 13 via Heck reaction on solid support proceeds more rapidly than the corresponding solution phase reaction 22 (Scheme 1.6.5).

47


Scheme 1.6.5

Reagents and conditions:

i) Pd(OAc)2,PPha,Bu4N§ -, DMF/H20/NEt3,37~ 4h.

Treatment of the hydroxy acid 15 with methyl azodicarboxylate resin 17 yielded lactone 16 in 42% yield.21 The comparable reaction with soluble azodicarboxylate gave 16 in 8% only (Scheme 1.6.6). Scheme 1.6.6

~O

~ ~O

' /

0

HO'~ O

/

-

0 "

CO2H ~ , ~

15


48

0

~

0

~

0 16 (42 %)

i) 17, PPh3,r.t., 48h


On the other hand, Story et al. 153 reported an unsuccessful attempt to prepare ten membered lactam ring 19 on solid support (Scheme 1.6.7); the HBTU mediated coupling produced linear products such as dimer (21) instead. Scheme 1.6.7

Reagents and conditions: i) a) HBTU, HOBt, DMF/DMA (1:1 ), DIEA, 2h, b) piperidine

1.6.2. Multipolymer systems 1.6.2.1. Insoluble polymeric reagents An important property of polymeric reagents was described by Rebek et al. 137 and Cohen et al., 154 namely that functional groups bound to different insoluble polymers cannot react with one another, as only a negligible number of reactive sites is located on the outer surface of the beads. Thus, two or more otherwise incompatible reagents such as acid / base 155 or oxidant / reducing agent 156 immobilised on a polymeric support, may be simultaneously used in the same reaction compartment.

49


For mechanistic investigations, Rebek introduced the three-phase method, 137,157-159 which is based on the site isolation of reactive groups. The test system consists of two polymers which can -

if necessary - be separated by a frit or distinguished by particle size. An intermediate is released

from the fh'st polymer (polymeric substrate) by action of a soluble reagent. The second polymer suspended in the same solution is used to trap the intermediate. Any observed reaction between the two solid phases requires free intermediates in solution and the method therefore supplies evidence for their existence (Scheme 1.6.8). The structure of the intermediate may be revealed indirectly by cleavage of the product from the second polymer followed by spectroscopic investigation. Such polymer systems are particularly well suited for elucidation, whether a given reaction is proceeding via an intramolecular or through a dissociative mechanism involving free intermediates. 16~

Scheme 1.6.8

Cohen eta/. 144,154provided the first synthetic application for the simultaneous use of antagonistic

reagents. A two polymer system consisting of a strong base and an active ester was used to acylate enolates derived from ketones, nitriles, secondary amides or esters. The benzoylation of acetophenone 22 for example (Scheme 1.6.9) produced the ~-diketone 23 in 96% yield, whereas the control reaction with soluble reagents afforded only 48% of 23. Since the diketone 23 is more acidic than the starting ketone, the latter is reformed by proton exchange with the product and the yield of the reaction in solution does therefore not exceed 50%. 137 Unlike their soluble anlogues, polymeric Irityl lithium and polymeric active ester do not interact in suspension and excess of the base can thus be used to obtain complete conversion.

50

1.6. Solid-supportedreagents

Scheme 1.6.9

Dioxolan protected ketones 24 and aromatic or t~,13-unsaturated aldehydes were hydrolysed and directly transformed into olefins using an acidic cation exchange resin and a phosphonate resin in aqueous THF 155 (Scheme 1.6.10). Again, such a combination of reagents would be impossible in solution as the ylide would neutralise the acid catalyst.

Scheme 1.6.10

Until now, only a few synthetic examples have been described using a combination of more than two polymeric reagents either simultaneously or sequentially. Such methods avoid the isolation of intermediates and thus improve the efficiency of a particular reaction sequence. An early example was based on Cohens 13-diketone synthesis (Scheme 1.6.11) and involved treatment of product 23 with a hydrazinium cation exchange resin to generate pyrazole 26.154

51


Scheme 1.6.11

Recently, Parlow 161 presented a synthesis of tx-substituted acetophenones using three polymeric reagents sequentially or simultaneously (cf. Chapter 3.5.5)

1.6.2.2. Soluble and insoluble polymeric reagents Unlike reagents bound to crosslinked polymeric supports, soluble macromolecules are able to interact with reactive groups attached to insoluble polymers. This fact was demonstrated by Frank and Hagenmaier, 162 who developed an alternating liquid-solid phase peptide synthesis procedure.

Amino acids attached to crosslinked polystyrene via a carbamate linker were condensed with a peptide ester of polyethyleneglycol monostearylether (Scheme 1.6.12). Scheme 1.6.12

52


A related example was provided by Jung and coworkers, 163 who reacted the insoluble polymeric active ester 27 (Scheme 1.6.13) with the free amino group of a soluble aminoacid- or peptide polyethyleneglycol ester 28.

Scheme 1.6.13

Reagents and conditions: i) N-methylmorpholine, CH2CI2" ii) HCI / AcOH / H20

Han and Janda 164 prepared the soluble polymeric monomethyl-polyethyleneglycol derived catalyst 29, which was used in asymmetric dihydroxylation of the TentaGel| attached cinnamic acid ester 30 to produce the diol 31 with high e.e. (Scheme 1.6.14).

Scheme 1.6.14

Reagents and conditions: i) 29, OsO4, K3Fe(CN)6, K2CO3, CH3SO2NH2, tBuOH / H20 (1:1 ),

r.t., 24h; ii) NaOMe, MeOH

53


Sterically more demanding soluble polymeric species, however, might be kinetically isolated from the reactive sites of crosslinked macromolecules. This was demonstrated by Bergbreiter and

Chandran, 165 who described a concurrent alkene reduction and alcohol oxidation, using the soluble polymeric Rh(I) hydrogenation catalyst 32 and poly(4-vinylpyridinium chlorochromate) (PVPCC) as a stoichiometric oxidant (Scheme 1.6.15). A control experiment proved, that

Wilkinson's catalyst (C1Rh(PPh3)3) could not replace the polymeric catalyst as the Rh(I) as well as the triphenyl phosphine ligands were rapidly oxidised. The polymeric catalyst was inactive only after being exposed to PVPCC over 40 hours. The size of the bulky macromolecular catalyst seems to be sufficient to allow only very slow diffusion of the catalyst into the matrix of the insoluble polymeric oxidant and the much faster proceeding hydrogenation is therefore completed before desactivation of the catalyst.

Scheme 1.6.15

[

OH

i)

{ ,CHO

CI Fltt ....PPh2CH2-PEG PEG-H2CPh2 P~ 9 PPh2CH2-PEG 32

Reagents and conditions: i) 32, PVPCC, H2, xylene, 100~

12h, 80%

1.6.3. Application of functionalised polymers to purification Polymeric reagents can be used to selectively remove a component from a mixture. This is effected by attachment of the compound in question to a solid support, subsequent filtration, and - if necessary - release from the support. The most classical examples of this application of crosslinked polymeric reagents were provided by

Frdchet and comprise the separation of cis and trans 1,2-diols (cf. Chapter 3) and the isolation of cis 1,3-diols from crude reaction mixtures using polystyrylboronic acid resin 166 (Scheme 1.6.16).

54


Scheme 1.6.16

Reagents and conditions: i) Na / EtOH; ii) H20

Carpino et al. 167,168 presented polymer-bound piperazines 33 which caused deblocking of Fmoc

amino protective group with subsequent scavenging of the released dibenzofulvene to give 35, affording essentially pure amine 34 (Scheme 1.6.17). Scheme 1.6.17

55

1. Introduction,basic conceptsand strategies

Functionalised polymers may simplify the isolation of an isomer in case of non-specific transformations. Crowley and Rapoport 169 described the Dieckmann condensation of solid-supported radiolabeled

mixed diesters 36 (Scheme 1.6.18) which afforded two 13-ketoesters, one being released into solution and the other staying grafted onto the polymer.

Scheme 1.6.18

Reagents and conditions: i) (Et)3COK, toluene, 110~

AcOH.

Leznoff and Svirskaya 17~ achieved the synthesis of nonsymmetric tetraaryl porphyrine 39 (Scheme 1.6.19) on solid support. The polymer-bound product 37 was separated from the soluble

symmetric porphyrin byproduct 38 by continuous extraction and 39 was finally released by methanolysis of the ester linkage.

56

1.6. Solid-supported reagents

Scheme 1.6.19

39

Reagents and conditions: i) propionic acid, A; ii) continuous extraction; iii) K2CO3, MeOH.

During the last two years the interest in separation techniques based on reactive polymers had a renaissance and many applications of supported quenching reagents in solution phase paraUel syntheses were described. Ion exchange resins 171-174 as well as polymers with covalently attached reactive groups 175-178 were used to selectively trap either reaction products or contaminants. Excess of a reagent is usually removed by polymers bearing functional groups which mimic the reactivity of the starting material (cf. Scheme 1.6.20 for general representation; for detailed discussion of specific examples see Chapter 3).

57


Scheme 1.6.20

By simplifying workup and purification procedures, polymeric reagents may help to circumvent the major obstacle to solution phase parallel syntheses. Separation by supported reagents is based on the chemical reactivities of the components of a mixture rather than on their physical properties. Therefore, this method can be used to purify library mixtures where conventional techniques such as chromatography, crystallisation or precipitation are no longer applicable. Mixtures of ureas were generated by reacting mixtures of amines with excess of an isocyanate and subsequent removal of remaining reagent using aminomethyl polystyrene 179 (Scheme 1.6.21). Scheme 1.6.21

Reagents and conditions: i) CHCI3, r.t.

58


Supported reagents were further applied to achieve post-cleavage purification of products obtained by solid-phase synthesis. This is illustrated by an example from Ellman's laboratoryl80 (Scheme 1.6.22). The 13-turn mimetic precursor 43 was released from solid support by TCEP (41) mediated cleavage of a disulfid linkage. The polymeric guanidine 44 was used to remove excess of 41 and of the phosphinoxide 42, to promote formation of the cyclic sulfide 45, and to trap the byproduct HBr from solution. Scheme 1.6.22

59


1.6.4. Polymer-supported reagents and catalysts In general, polymer-supported reagents are used in excess. On one hand, it should be considered that not all functional groups are solvent-accessible which is important if the loading of a polymer was determined by elemental analysis. On the other hand, however, polymers may adsorb products. Hence, there is some optimal amount of reagent to be applied. Polymeric reagents are not always used in the same solvents as their low-molecular weight analogues. Chromate supported on ion exchange resin for example gave best results when used in cyclohexane rather than in CH2C12,181 and polymeric perbenzoic acid performed better in THF than in CH2C12.182 Macroreticular ion exchange resins are often used in apolar solvents (benzene, toluene, hexane, pentane) to which ionic groups are well exposed in the permanent pores of the material. Such resins are offering an alternative to classical phase transfer conditions. 183,184 Most of these ion exchange resins are commercially available.

Some of the most widely used solid-supported reagents and catalysts are summarised in the following tables: Table 1.6.1. Solid-supported nucleophiles Table 1.6.2. Solid-supported electrophiles Table 1.6.3. Solid-supported oxidants Table 1.6.4. Polymer-supported reducing agents Table 1.6.5. Polymer-supported coupling and dehydrating agents Table 1.6.6. Solid-supported halogen-carriers Table 1.6.7. Polymeric bases Table 1.6.8. Reagents derived from polystyryl diphenylphosphine Table 1.6.9. Chiral polymer-bound catalysts Table 1.6.10. Miscellaneous reagents

60


Table 1.6.1. Solid-supported nucleophiles structure

preparation

X-=F-

application

From Amberlyst| A-

Nucleophilic displacement of halides or sulfonates in

26 (C1-) or

primary or secondary substrates affording fluorides.

Amberlite| IRA 900

Olefins are formed as by-products. 185,186

(C1-) by treatment

Halide displacement in a-haloesters and in a-halo

! with NaOH and HF185,186

methylketones. 185 Cleavage of diphenyl-tert-butylsilyl ethers. 184 For other applications cf. Table 1.6.7

X- = CN-

From Amberlyst| A-

Synthesis of nitriles from alkyl and acyl halides 187

26 (C1-) by treatment with aq. KCN 187 X- = SCN-

From Ambedyst | A-

Thiocyanates or isothiocyanates were obtained from

26 (C1-) by treatment

primary or secondary alkyl halides. 187

with aq. KSCN187,188

were prepared from the corresponding acid

Acyl isothiocyanates or sulfonyl isothiocyanates chlorides. 187

X - = NCO-

From Amberlyst| A-

Symmetrical N,N'-dialkyl ureas from primary and

26 (C1-) by treatment

secondary as well as from benzylic and allylic

with aq. KOCN 188

halides if the reaction was performed with wet resin in apolar solvents. 188 N-Substituted ethyl urethanes were obtained from alkyl and benzyl halides if the reaction was carried out in EtOH.

X - = NO 2- From Amberlyst~ A26 or Amberlite| IRA

Synthesis of nitroalkanes and alkyl nitrites from alkyl halides. 189,190

400 From Amberlite~ IRA a-Nitro carboxylic esters from a-bromo esters;

X - = Ph-Se-

900 (C1-) by

alkyl-nitro compounds from primary, secondary and

treatment with

benzylic bromides (formation of nitrites was not

NaNO z soln. 183

detected). 183

From Amberlyst| A-

Organyl phenyl selenides were prepared from alkyl

26 (BH4-) by

iodides, allyl bromides, a-bromo esters or benzyl

treatment with

halides. 191

(PhSe)zl91

61


Table 1.6.1. Solid-supported nucleophiles (continued)

structure

preparation

X - = Ar-O-

application

From Amberlite| IRA Aryl alkyl ethers and heteroaryl alkyl ethers from alkylhalides. 171,183 900 (C1-) by treatment with NaOH and ArOH in EtOH. 171 From Amberlite | IRA Diaryloxymethanes from dichloromethane. 192 400 (C1-) by treatment with ArONa soln.192 From Amberlyst| A-

Alkyl aryl ethers from alkyl sulfonates 193

26 X - = AcO-

Amberlyst| A-26

Acetates from prim. iodides; 193 acetamido diols from iodo amino alcohol hydrochlorides (via aziridines). 194,195 NH3+CIHOv.,L,,,./R I

X- = Ar-COf

NHAc ~ HOveR OH

OH + HOv,~R | NHAc

From Amberlite | IRA Synthesis of acetonylesters from chloroacetone

X - = Ph-CH2-CO 2- 400 (C1-)196 X-=PhCH=CHCO 2X - = CO32-Na+ From Amberlyst| A26 (C1-) by treatment

Synthesis of alcohols from primary, benzylic and allylic halides. 197

with Na2CO 3 soln. 197 RO, ,(3 ROP~.....

X

_ Z

-

-

.

From Amberlyst| A26 (CI-) 155

_

Wittig reaction; E-isomer or mixtures of E/Z-isomers

were obtained. 155

z= CN, COzMe From PTBD-resin

Alkyl aryl ethers from primary, allylic and benzylic

(cf. Table 1.6.7,

bromides as well as from ct-bromo ketones, esters

polymeric bases) by

and amides. 198

treatment with ArOH

Bis-aryl ethers from aryl fluorides. 198

in MeCN. 198

62

Olefins from aldehydes and ketones by Horner-


Table I h.1. Solid-supported nucleophiles (continued)

I preparation

i!mCture

From chlommethyl polystyrene by treatment with tris(2-

application

Scavengers; 10 remove excewes of isocyanates, carboxylic acid chlorider or sulfonyl chlorides from reaction rnixiure~176-177.179

aminoethy1)aminein

NM2

Table 1.6.2. Solid-supported electrophiles

-N=c=Q cot,

preparation

application

I

From aminomethyl polyseene by

Scavenger; to remove excess of p r i m q amine from reaction mixture (reductive a m i n a t i ~ n ) . ~ ~ ~ Scavenger: ‘to separate secondary amines from tertiary amines.177

,

triphosgene.’’’ From carboxylated polystyrene by

treamnt with

Scavenger, to separate secondary arnines from tertiary amines.176

m a m n t with

s OCL.199

0

9 Q...H

From polymersupponed arnines by trcamnt

with

CSJrsCl or with CSCfp0

NCS

63


Table 1.6.3. Solid-supported oxidants

64


Table 1.6.3. Solid-supported oxidants (continued)

Scheme 1.6.23

CrO3 (solid) + Bu4 N+CI-

CH2CI2

---

Bu4N+CICrO3-

Treatment of quarternary ammonium chloride resins in the presence of a phase transfer catalyst in a solidliquid-solid system (one pot procedure)

65


Table 1.6.4.

66

Polymer-supportedreducing agents


Table 1.6.4.

Polymer-supported reducing agents (continued)

Table 1.6.5.

Polymer-supported coupling and dehydrating agents

67


Scheme 1.6.24

Reagents and conditions: i) R-N=C=O, THF or CH2CI2/ Et20; ii) TsCI, NEt3, CH2CI2, 40~

or TsCI, pyridine, 70~

68

iii) EDC, DMF, 100~ 15h.


Table 1.6.6.

Solid-supported halogen-carriers

69


Table 1.6.7. Polymeric bases

70


Table 1.6.7. Polymeric bases (continued)

Scheme 1.6.25

Scheme 1.6.26

71

I . Introduction, basic concepts and strategies

Table I .6.8. Reagents derived from polystyryl diphenylphosphine

1 appl icaiion

prepan tion

;tmcrure

Treatment of polystyryl diphenyl phoyhine” with al kylhalides

It’ifii,? reaction

Cis I fruits stilbene from benzaldehyde.?4’ Olefins from aromatic and aliphatic aldehydes and

R = ph: X = CI R = H.CH,. Ph: X = 1. Br

Mono-olefinr from rerephthaldehyde and iso-

R = Ph: X = CI. Br R = C02Mc:X = Br

qFI

3

X-Br

M

phthaldehyde (ylide generation by meanent of knzyyl diphenyl polyqtyrylphosphonium bromide with ethylene oxide afforded mono ethylene acetals m byproducts).~d~ From polystyryl Synthesis of ethylretinoate (48) from aldehyde 49 diphen ylphosphine (Scheme I ~ 5 . 2 7 ) ~ ~ ~ and p-cyclogeranyl bromide of ;P-geraniol (cf. Scheme

1.6.27)2d5 R = H . P h From polystyryl diphcny lphosphine crosslinked with 2.8 auu ~ w - mu v

D.

Comparison of olefin formation from aldehydes and ketones using polymeric phosphonium halides with different degree of crosslinking. * 5

- --

Amides from primary amines and Cbz-, Boc- or Fmoc-protected a-amino acids. No epimeriisetion was

CCI,

detected (detection limit 2nC)?46 Alkyl chlorides from primary. s e c o n d q and benzylic

alcoh~~s.~~~ Tmhnent Of p l y styryl diphenylX = CI. Rz. 1 phosphine with CI:. Br, or 1: in

CH,CI,.’-’R

Halohydrins from epoxidcs: yields and selectivitieq compare well with those obtained with monomeric triphen yl phosph i ne-halopen complexes.? Open and cyclic acetalq and t h i o x e u k by treatment nf aldehydes and keroneq with alcohols or thiol? in thc presence of polyrtyryl diphenylphocphine indine comple K ,249

a) Polystyryl diphenylphosphine was prepared from bromo-polystyrene1 or by copolymerisationof styrene, pstyryl diphenylphosphineand DVB243

1592439244

72

as outlined in Scheme 1 S.4.10


Scheme 1.6.27

Table 1.6.9. Chiral polymer-bound catalysts (Structures, see Figure 1.6.1) structure 52 / tfiallylborane

preparation

application

Copolymerisation of

Enantioselective synthesis of homoallyl amines by

monomeric precursor

allylation of N-trimethylsilyl benzaldehyde imine (Scheme 1.6.28). 250

51, styrene and DVB (1:8:1) and treatment of the polymer with triallyl borane prior to use (Scheme 1.6.28) 250 53 / Et2Zn

From chloromethyl polystyrene and (-)ephedrine. 221

Enantioselective addition of Et2Zn to aromatic and aliphatic aldehydes. 251 enantioselective alkylation of N(diphenyl)phosphinoyl imines 252 (Scheme 1.6.29)

54 / EtEZn

Treatment of 6-

Enantioselective addition of Et2Zn to benzaldehyde

iodohexyl-polystyryl

(cf. Chapter 3.6.3)

ether with (1S,2R)N-butyl norephedrine 253

73

1. Introduction,basic conceptsand strategies Table 1.6.9. Chiral polymer-bound catalysts (continued) structure

preparation

application

55 [ Ti(OiPr) 4 ]

From chloromethyl

Enantioselective addition of Et2Zn to benzaldehyde

Et2Zn

polystryene or by co-

(cf. Chapter 3.6.3).

polymerisation of the

Enantioselective Diels-Alder reactions (cf. Chapter

chiral monomer with

3.6.3). 254

styrene or DVB. Subsequent transformation into solid-supported TiTADDOLates. 254 (cf. Chapter 3.6.4)

56

Catalyst in three component coupling of aldehydes, aromatic amines and olefines affording quinolines (cf.

Chapter 3.6.4). 255 Chemoselective addition of silyl enol ethers to imines in the presence of aldehydes. 256 57 [ BH 3

I

OsO 4

1.6.30). Yields are comparable but enantiomeric

monomer with

excesses are lower than those obtained with the

styrene and DVB.257,258

soluble Ts-Val-OH. 257 Catalyst for Diels-Alder reaction of cyclopentadiene and methacrolein (Scheme 1.6.30).257 Enantioselective epoxidation of styrene and cis-fS-

the monomeric

styrene using various oxidants. 141

divinyl substituted

Cis / trans ratio of epoxides range from 73:27 to 93:7;

Mn complex with styrene and DVB. 141

enantiomeric excesses from 4 to 41%.

Copolymerisation of

Asymmetric dihydroxylation (cf. Chapter 3.6.1).

1,4-bis(9-quinyl)-

other polymer-supported catalysts for asymmetric

phthalazine with

dihydroxylation have been presented in the recent literature. 259-266

methyl methacrylate. 142

74

Promotor in Mukaiyama aldol reactions (Scheme

the vinyl-substituted

Copolymerisation of

58

59 /

Copolymerisation of


Figure 1.6.1

75


Scheme 1.6.28

Scheme 1.6.29

R = phenyl: 80% yield, 80% e.e. R = naphthyl: 61% yield, 85% e.e.

76


Scheme 1.6.30 OR

0

O

57 / BH3THF ~'

OEt

THF or CH2CI2 R=H, TMS

"•CHO +

[~

57 / BH3DMS THF / CH2CI2

,•CHO

89 % yield, 65 % e.e. (endo / exo 1:99)

Table 1.6.10. Miscellaneous reagents

structure

preparation

application

From hydroxymethyl

Mitsunobu reactions: esters from carboxylic acids and

polystyrene by alcohols; lactones from hydroxy acids; N-alkylation treatment with COC12, of phthalimides, ~-alkylation of cyanoacetate; H2NNHCO2Me and

carbodiimides from thioureas. 21

NBS or C12.21 Lithiation of bromo polystyrene and

Epoxides from aldehydes and ketones under phase transfer conditions. 267

subsequent treatment with alkyl disulfide and alkylation. 267 From polystyrene in 3 Preparation of polymeric activesters by reaction with steps (Scheme 1.6.31). 268

N-protected amino acids and DCC. 268 Synthesis of medium ring lactams by coupling o~amino acids to the HOBt resin and subsequent cyclisation. 269

Treatment of

Hydrofluorination of alkenes (---)fluorides) and

crosslinked poly-(4-

alkynes (---)gem. difluorides). 27o

vinylpyridine) with

Alkylfluorides from sec. and tert. alcohols. 27o

anhydrous hydrogen

Treatment of alkenes with the polymeric HF-

fluoride. 270

equivalent in the presence of NBS afforded vic. bromofluorides. 27o

77


Scheme 1.6.31

78


1.6.5. Polymer-supported chiral auxiliaries In the context of library generation the ever-growing interest in asymmetric synthesis on solid phase is documented by various recent publications. 271-276 In contrast to polymeric chiral catalysts and reagents presented in Tables 1.6.1-1.6.10 interacting with soluble substrates, supported chiral auxiliaries are used as linkers to attach substrates and products to the polymer and act as source for optical induction. Chiral auxiliaries are regenerated at the end of a reaction sequence. It is therefore particularly attractive to attach these expensive reagents to crosslinked polymers, thus facilitating their recovery as well as the isolation of reaction products. Asymmetric syntheses using polymeric auxiliaries allowed further to investigate the steric influence of the polymer backbone on the diastereoselectivity of a given transformation.

Scheme 1.6.32

Reagents and conditions: i) phenylglyoxylic acid, py, benzene; ii) MeMgCI, Et20, benzene;

iii) KOH, MeOH/H20; iv) filtrate; v) HaO §

Early examples of such studies date back to the seventies. M. Kawana and S. Emoto 277,278 achieved a synthesis of atrolactinic acid 60 using a polymer-bound D-xylose derivative as auxiliary (Scheme 1.6.32) to which phenylglyoxylic acid was attached via an ester linkage. Addition of MeMgBr to the chiral ester was the key step of the sequence. Leznoff and coworkers279, 28o immobilised cyclohexanone via imine formation with a polymeric chiral amine and investigated the (t-alkylation (Scheme 1.6.33). Both groups reported optical yields at least as high as in the comparable solution phase reactions and found that their polymeric auxiliaries could be re-used successfully after recovery.

79


Scheme 1.6.33

Reagents and conditions: i) cyclohexanone, benzene, molecular sieves;

ii) LDA, THF, O~ iii) R-I, r.t.; iv) H30§ Colwell et al. 281 studied the o~-benzylation of polymeric oxazoline 61 and obtained optically active

ester 63 after ethanolysis (Scheme 1.6.34). The chemical yield of 63 was poor due to incomplete cleavage. The recovered polymer consisted of amino alkohol 64, amino ester 65 and oxazoline 62. Recycling of the chiral polymer-bound auxiliary was therefore difficult. Scheme 1.6.34

Reagents and conditions: i) nBuLi, BnCI, THF; ii) H2S04, EtOH

80


The synthesis of 7-butyorolactones was achieved by Kurth et al. 271,272 by ot-alkylation and subsequent iodo-lactonisation of N-acylated chiral amines (Scheme 1.6.35). Pyrrolidine 67 272 was more selective in both alkylation and cyclisation as supported L-prolinol 66. 271 Both chiral polymers were re-usable.

Scheme 1.6.35

Reagents and conditions: i) LDA, THF, 0~

30 min; ii) allyl iodide; iii) 12,THF, H20

Polymer-bound Evans oxazolidinones were recently studied by several groups. 274-276 Burgess and Lim 275 compared the benzylation of propionylated auxiliary 71 attached to MerrifieM resin 70a, Wang resin 70b and TentaGel | R PHB 70c, respectively (Scheme 1.6.36). Products 7 3 were released by reductive cleavage. In terms of yields and enantiomeric excesses, best results were obtained with the Wang resin supported auxiliary. Furthermore, prolonged reaction times resulted in decreased yields. Other electrophiles such as isopropyl bromide and benzyloxymethyl chloride gave lower chemical yields. Comparably low diastereoselectivity was observed when the benzylation was performed with the auxiliary directly attached to Merrifield resin. This is in contrast to the results obtained by Shuttleworth and Allin 276 who reported high diastereoselectivity for the benzylation of supported serine-derived N-acyl oxazolidinone 74. 81


Scheme 1.6.36

Reagents and conditions: i) KOtBu, 18-Crown-6, Bu4N*I, DMF; ii) PPh3, DEAD; iii) LDA (3 eq), 0~ iv) BnBr (5 eq), 0-25~ v) LiBH4; vi) LDA (2 eq), THF, 0~ vii) BnBr; viii) aq. NH4CI; ix) LiOHH20, THF, H20

Polymeric Evans auxiliary 76 was also applied to aldol reactions 274 (Scheme 1.6.37). In a model reaction, immobilised dihydrocinnamic acid was converted into the boron enolate and reacted with isovaleraldehyde. Products were released by treatment of the resin with NaOMe. The [3-hydroxy ester 79 was obtained in a 20:1 diasteromeric ratio, along with some ester 80 derived from unreacted starting material.

82

1.6. Sofid-supportedreagents

Scheme 1.6.37

Reagents and conditions:i) LiHMDS, THF, Ph(CH2)2COCI;ii) nBu2BOTf, DIEA, CH2CI2,-20~

iii) isovaleraldehyde,-20~

iv) H202, DMF; v) NaOMe, THF,-20~

Reggelin and Brenig 273 reported a different approach for the asymmetric synthesis on solid support (Scheme 1.6.38). An acylated Evans auxiliary was used as a soluble reagent for the transformation of polymer-supported aldehyde 81 into imide 82. The latter was converted into the

Weinreb amide 83 which was - after protection of the hydroxyl group - submitted to DIBAH reduction to generate aldehyde 84. The configurational course of the reaction was studied by liberation of diastereomers 85 from the polymer 82.

83


S c h e m e 1.6.38

Reagents and conditions: i) pySO3, DMSO, NEt3; ii) H202, MeOH; iii) Me3AI, MeNH(OMe)HCI;

iv) TIPSOTf, 2,6-1utidine; v) DIBAH; vi) HCI/EtOH" vii) BCI3, CH2CI2;-78~

84

1.7. Linker molecules and cleavage strategies

1.7. L i n k e r

molecules

and cleavage strategies

1.7.1. Introduction Linker molecules play a key role in any successful synthetic strategy on solid phase as they covalently link the polymeric support and the molecules that are synthesised. Linkers are usually bifunctional spacer molecules which contain on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures. Whereas linkers were traditionally designed to release one specific functional group, e.g. carboxylic acids and amides in peptide synthesis, the synthesis of small-molecular-weight compound libraries has required additional linker- and cleavage strategies. Among those, the use of traceless linkers and linkers that allow cyclisationassisted and multidirectional cleavage have emerged as powerful tools in solid-phase organic synthesis. Since a given linker molecule has to be chemically inert during the construction of the target molecules and thus be resistant to a wide variety of reaction conditions, the so-called "safety-catch" linker principle was rediscovered for combinatorial synthesis. A "safety-catch" linker is usually converted from a chemically inert entity into a reactive species in the very last step before cleavage. This rather intriguing strategy allows most of the time multidirectional cleavage procedures, which will be discussed in Chapter 1.7.4 and constitutes one of the most useful tools in COS. Consequently, we have grouped linker molecules and strategies into the following sections: 9 Linker molecules releasing one specific functional group ("monofunctional cleavage") 9 Cyclisation-assisted cleavage strategies 9 Multidirectional cleavage strategies - by direct nucleophilic or electrophilic substitution

- using "traceless" linkers - by activation of the linker molecules ("saftey-catch principle")

1.7.2. Linker molecules releasing one specific functional group Monofunctional resin-cleavage has found high attention in the field of organic synthesis on solid support and many excellent compilations have emerged in the recent literature. 282-284 Monofunctional resin-cleavage strategies are well suited for the construction of focused combinatorial libraries, where a given important pharmacophoric group which remains constant is released in the very last step. Hence, the linkage to the resin serves as a protective group

85

1. Introduction,basic conceptsand strategies throughout the synthesis. We have classified the linker groups according to the functional groups that are released from the resin in the following order: 9 carboxylic acids (Table 1.7.1) 9 amides (Table 1.7.2) 9 sulfonamides (Table 1.7.3) 9 hydroxamic acids (Table 1.7.4) 9 amines (Table 1.7.5) 9 alcohols and phenols (Table 1.7.6) 9 miscellaneous

Carboxylic

acids

The largest number of linkers have been certainly described for the release of carboxylic acids and amides as they are closely related to peptide synthesis. Nevertheless, carboxylic acids play an important role in drug discovery and many prominent classes of pharmacologically active compounds such as aryl acetic acids (e.g. present in Voltaren*), 2-aryl propionic acids (e.g. present in Naproxen *) used as non-steroidal antiinflammatory agents, angiotensin converting enzyme (ACE) inhibitors such as Vasotech| or antibiotics such as Ciproxin | and Ceclor| contain this moiety (Figure 1.7.1).

Figure 1.7.1

MeOOC HOOC,, O

.COOH ~COOH

vasotec| COOH O.

N

CI

0 Ciproxin|

i,,,.COONa H CI ~ , O , ~ ~

-

NH2

H

Ceclor~

86

0

Voltaren|

Naproxen|

CO2H


In Table 1.7.1 some of the most widely used linkers to release carboxylic acids are grouped. The

first family of linker groups (entries 1-8) comprise groups that can be cleaved under acidic reaction conditions. Entries 9-15 show examples of linkers that are cleaved under basic, entries 13 and 16 under neutral and palladium-catalysed conditions. Finally, entries 17-20 depict the class of photocleavable linker groups playing an increasingly important role in COS.

Table 1.7.1: Release of carboxylic acids

87


Table 1.7.1: Release of carboxylic acids (continued)

a) X=O, NH

88


Amides

Similarly to the release of carboxylic acids, amides have been grouped according to acidic and photochemically cleavable linkers (Table 1.7.2) Table 1.7.2: Release of amides

89


Table 1.7.2: Release of amides (continued)

a)X=O, NH

Sulfonamides Sulfonamides are a pharmacologically important class of molecules. Indeed, many prominent drugs 313 contain this functional group as depicted in Figure 1.7.2. Figure 1.7.2

~o

I

%~o

oA N

H2NS~~'NH H

Thiazide| (diuretic) ~N

Accolate|

NH

O O H,N'~-~I SO2NH2

Dorzolamide |

(used in treatment of glaucoma, eye desease)

(3,, ,(3

H2N~ M&B 693

(antibacterial)

Sulthiamine| (carbonic anhydrase inhibitor)

Some of the most useful linker molecules for the release of sulfonamides are depicted in Table 1.7.3.

90


Table 1.7.3: Release of sulfonamides

Further sulfonamide linkers can be found in the literature. 316,317

Hydroxamic

acids

Hydroxamic acids have emerged as an important class of inhibitors of matrix metalloproteinases (MMP's) such as collagenase, gelatinase and others. 28 MMP' s are becoming prime targets in many therapeutic areas (e.g. antiinflammatory and anticancer agents). In Figure 1.7.3 are depicted several drugs or development candidates containining a hydroxamic acid moiety. Figure 1.7.3

HO- N H

.o~

o

-V~N/. H

._~~~ o o

HO- N H $j

0

V~N/. : H -

Galardin |

S~

Batimastat|

0 j

oo=~=o~ H

~

HO.N.0~ N N ~

~.~o- ~ I

CGS 27023

Ro 32-3555

91


Therefore, linker molecules releasing the hydroxamic acid moiety are most valuable tools for the construction of targeted libraries for interactions with MMP's (Table 1.7.4)

Table 1.7.4: Release of hydroxamic acids

Amines

The linker groups releasing amines are depicted in Table 1.7.5 and grouped according to their releasing reaction conditions.

92


Table 1.7.5: Release of amines

93


Alcohols, diois and phenols Various linker strategies for the attachment of alcohols and phenols have been devised and the most recent examples are listed in Table 1.7.6.

Table 1.7.6: Release of alcohols, diols and phenols

L entry i, structure

abbreviation

cleavage conditions

references, comments

TFA / CH2C12

291

TFA / CH2C12

331

PPTS / EtOH TFA / CH2C12

322

4

TFA / CH2C12

287

5

TFA / CH2C12

H3O+

5

H3O+

5

HF, anisole;

332, 333, 334

, NH 3 or NH2NH 2

1 LiBH 4

10

94

Bu4NF, CsF

335

297


Table 1.7.6: Release of alcohols, diols and phenols (continued)

Miscellaneous Release of guanidines

Refs. 337,338

Release of aldehydes

Ref. 335

Ref. 5

Release of phthalazinones

Ref. 339

95


1.7.3. Cyclisation-assisted cleavage Among the various cleavage strategies described in the literature there is an increasingly important number dealing with cyclisation-assisted cleavage procedures. One of the first examples was the pioneering benzodiazepine synthesis of Camps and coworkers 34o in 1974, where the final benzodiazepine ring formation occurred by simultaneous cleavage from the resin. Many applications of this principle have appeared and some of the most recent examples will be discussed in Chapter 4. Cyclisation-assisted cleavage offers the following advantages: 9 Only molecules that have gone through the whole reaction sequence necessary for the cyclisation reaction will be cleaved. 9 Even if the single reaction steps do not proceed quantitatively, the cyclisation will nevertheless lead to pure products. As expected, cyclisation-assisted cleavage is largely independent of the nature of the linker molecule but rather depending on the synthesis that is necessary to create the precursor molecules. Therefore, it is not surprising that many linkers are compatible with cyclisation-assisted cleavage procedures. Nevertheless, Figure 1.7.4 shows some of the most prominent examples of this methodology. Figure 1.7.4

96


Reagents and conditions: i) Davies reagent; ii) trichloroacetic anhydride; 341 iii) DMAP, toluene; 342 iv)

acryloyl chloride, NEt3, CH2CI2;v) R1-NH2; DMSO; vi) R2-N=C=O; vii) HCI, toluene, 95~

viii) TFA; 344 ix)

BrCN, TFA, CHCIJH20. 345

97


1.7.4. Multidirectional cleavage strategies Monofunctional resin cleavage procedures are well suited for the generation of targeted libraries where the key pharmacophoric group remaining constant forms the link between the resin and the molecules that are built up. Multidirectional cleavage offers the tremendous advantage that in the f'mal cleavage step an additional element of diversity is incorporated. Thus, the amount of compounds is multiplied by the number of elements that can be incorporated (see Figures 1.9.1 and 1.9.2, Chapter 1.9). Most of these linkers which have been described for multidirectional cleavage procedures are termed also as "traceless" linkers as no element of the linker remains in the final molecules. The main strategies include: 9 Direct cleavage by nucleophilic substitution reactions 9 Direct cleavage by electrophilic substitution reactions 9 Activation of the linker group prior to cleavage ("safety catch" principle)

1.7.4.1. Direct cleavage by nucleophilic substitution Figure 1.7.5 summarises the linkers and strategies that allow the final multidirectional cleavage from the resin using nucleophiles such as amines, alcoholates, thiolates and C-nucleophiles such as

Grig nard-reagents. Figure 1.7.5

98


Figure 1.7.5 (continued)

c:

Ketones from

Grignard-reagents and Weinreb-amides

99


1.7.4.2. Multidirectional direct cleavage by electrophiles Most of the linkers that allow multidirectional electrophilic cleavage from the resin are based on the chemistry of silicon. In Figure 1.7.6 are summarised some of the most interesting examples. Figure 1.7.6

Refs. 349,350

Ref. 111

Ref. 351

Ref. 352

100


1.7.4.3.

"Safety-catch" linkers

Among the successful linker strategies that are being developed specifically for the solid-supported synthesis of small organic molecules, the "safety catch" principle has become increasingly popular. Thereby, a linker molecule is activated in the very last step before cleavage. The major advantages are listed below: 9 During synthesis of the library the linker moiety is completely stable to a wide range of reaction conditions. 9 The linkage between the resin and the molecule can be specifically designed and planned in view of the structure and chemical stability of the final products. 9 The linker group can often be reduced to a single atom such as sulfur, tin, silicon and others

(vide infra). Thus, the rich chemistry and reactivities of these elements can be capitalised for the final activation and cleavage and can be integrated in the whole synthetic strategy. 9 The "safety catch" principle generally leads to multidirectional resin cleavage which allows multiplication of the final library members both in terms of structural and functional diversity.

The safety catch principle has been first described by Kenner et al. 353 in the field of peptide chemistry and was originally based on the reactivity of the sulfonimide group. Meanwhile, this concept has been used successfully by several other groups. Examples are listed in Figure 1.7.7. Activation of the polymer-bound sulfonimido group in 1 (Figure 1.7.7, entry a) was achieved by alkylation with diazomethane or iodoacetonitrile. Subsequent substitution with nucleophiles such as amines and alkoholates resulted in multidirectional cleavage to form products of type 3 in high yield. 353-355 The same products can be obtained by using active esters of type 4 (Figure 1.7.7, entry b) which are activated via oxidation to the corresponding sulfones 5 followed by nucleophilic cleavage. This strategy was successfully used in an intramolecular version to form cyclic peptides.

101


Figure 1.7.7

102


N u ~ O R 20

OR

Reagents and conditions: i) CH2N2or ICH2CN, DBU; ii) Nu- (amines or alcoholates); iii) m-CPBA, C1-12CI2;iv)

R3-X, DMF; v) DIEA, DMF; vi) base; vii) R2-CHO; viii) TFA; ix) Tf20, 2,6-di-tert-butyl-4-methylpyridine; CH2CI2, -60 to -30~ x) Hg(OCOCF3)2,CH2CI2,H20, r.t.

The REM-linker can also be regarded as a safety-catch linker (Figure 1.7.7, entry c). Activation of polymer-bound 6 was achieved by alkylation to form 7. Subsequent treatment with DIEA resulted in formation of the cleaved tertiary amines 8. 327,328 Polymer-bound phosphonium salts 9 form after activation with base the intermediate ylides 1 0 which can be multidirectionally cleaved by reaction with aldehydes R2-CHO to form products of type 11. 356

103


An elegant biomimetic acyl-linker was designed and synthesised by Frank et al. (Figure 1.7.7, entry e) based on the chemistry of imidazoles. Thus, Boc-protected polymer-bound imidazole 1 2 was activated by cleavage of the Boc-protective group. Acyl transfer and subsequent nucleophilic cleavage led products of type 3. 357,358 A novel safety-catch principle for the multidirectional cleavage of pyrimidines and related heterocycles was first developed by Obrecht eta/. 98,359 (Figure 1.7.7, entry f). Thus, polymerbound thiopyrimidines of type 15 are activated by oxidation to sulfones 16 with m-CPBA. Multidirectional cleavage was performed with various nucleophiles such as amines, alcoholates, azide and C-nucleophiles like CN- or malonates. Treatment of sulfones with ammonia or amines results in formation of pharmacologically interesting amino-pyrimidines. It is noteworthy that highly polar functional groups can be introduced in the very last cleavage step avoiding lengthy protective group manipulations. A similar strategy was recently described by Gayo and Suto. 36~ Another powerful sulfur-based safety-catch linker was developed by Kahne et al. 361-363 for the polymer-supported synthesis of oligosaccharides (Figure 1.7.7, entry g). Thio-linked saccharides can be efficiently cleaved from the resin in multidirectional fashion via sulfoxide 19 or by direct activation with Hg(OCOCF3) 2. These few recent examples impressively demonstrate the integration of the power of organic chemistry into the design and synthesis of linker and cleavage strategies for the creation of highly diverse, small "drug-like" molecule ensembles. Yet, there is much more to come in the future and it is easily imaginable that saftey-catch linkers will be the "winners" in this field.

104

1.8. Synthetic strategies in combinatorial and parallel synthesis

1.8. Synthetic strategies in combinatorial and parallel synthesis 1.8.1. Solution- versus solid-phase chemistry Since many advantages and disadvantages are associated with solution- and solid-phase chemistry we try to compare the pros and contras of the two strategies. We hope to be able to discern from this comparative study that the most efficient strategy to succesfully carry out parallel and combinatorial chemistry is to combine and integrate efficiently the strength and advantages of both methods in a given reaction sequence. As already pointed out in Chapters 1.3, 1.5 and 1.6, solid supported reagents and scavengers for excess of reagents are valuable tools for solution chemistry. In addition, reactions in solution can be complemented by additional solid-supported reaction steps.

solution chemistry ++

most reactions and reagents have been studied in solution

+

usually no excess of reagents have to be used

+

solvent effects can be studied and altered more readily

++

steric effects are usually less pronounced in solution and can be overcome more easily by using more drastic reaction conditions

++

reaction conditions are usually more easily adapted to a large variety of substituents extensive and time consuming, chromatographic purifications are often necessary

-+

side products have to be separated and analysed (can be also an advantage in the first

--

parallelisation and automation usually requires more initial effort

exploratory stage of a given project)

solution strategies will probably be more efficient for small libraries since less effort has to be put into method development

solid-phase chemistry ++

excess of reagents can be used to drive reactions to completion

++

purification procedures achieved by simple f'lltrations which can be easily automated

++

assuming complete spacial separation of the reactive sites on a given solid support, the principle of high dilution ("hyperentropic effect ''6) can be used beneficially e.g. for intramolecular cyclisation reactions

105


++

the costs have to be compared with the labour intensive extraction and purification procedures usually necessary in solution

+/-

linker molecules have to be designed which are compatible with the chemistry and the polymer matrix. Since the linker can be an integral part of the chemical strategy, this feature can also be advantageous.

-

reaction conditions have to be established for each case

-

the range of reactivity seems to be more restricted on solid supports than in solution

-

chemistry on polymers is relatively expensive: costs for the polymers, robotic systems and

-

reactions on solid support are more difficult to monitor

for the solvents have to be considered

aspects of using highly loaded resins especially critical for polymer-bound reagents and catalysts

i

irreversible binding of unpleasantly smelling and aggressive compounds high loading may lead to crosslinking reactions and thus interfere with the principle of high dilution crosslinking reactions can be essentially completely suppressed by using correctly designed linkers. high loading can be favourable for the reactivity of polymer-bound catalysts and reagents and also for intramolecular cyclisations and resin cleavage reactions

Solid-supported chemistry is very useful for the synthesis of larger series of compounds: investments in the development of methods will be paid off by faster production through simple robotic methods.

1.8.2. Compound mixtures versus single compound collections As pointed out earlier, combinatorial and parallel synthesis are used to synthesise mixtures as well as single compounds. When evaluating the advantages and drawbacks of mixtures and single compound collections it is important to consider the following aspects: 9 Type of compounds:- polypeptides, oligonucleotides, oligosaccharides - small carbocyclic and heterocyclic molecules

106

1.8. Syntheticstrategies in combinatorialand parallel synthesis ~ Type of library:

random libraries: large compound libraries consisting of highly

diverse compounds

(mixtures and single compounds) focused libraries: smaller compound libraries containing designed

elements of diversity

(single compounds preferred) lead optimisation libraries: small tailor-made compound

collections centered around a lead structure

(single compounds essential) 9 library format and assay throughput

As discussed and schematically shown in Figure 1.4.3 the lead discovery process is divided in several phases. In the very early phase of hit identification, where a large number of compounds are screened in the HTS, libraries usually consist of randomly selected compound collections where the structural and chemical diversity should be as large and random as possible. Many tools are available to date in order to assess qualitatively the degree of diversity present in a given collection (some of those will be discussed in Chapter 1.11). In cases where a high throughput screen is available, single compounds or mixtures can be screened. Several pharmaceutical companies store and test their compound collections for general screening purposes as cocktails (typically 10-50 compounds per cocktail), others screen only single compounds. Screening cocktails has the advantage that less biological material is necessary to screen the whole library. There are also many problems associated with the screening of cocktails. Synergic and non-synergic effects between compounds in the cocktail often complicate an unambiguous interpretation of the biological results. A pioneering study performed at Pfizer 14 revealed that mixtures above twenty compounds are prone to a lot of false positive results. The storage of mixtures can also be problematic due to possible degradation and chemical modifications of the products. In addition, the high degree of miniaturisation of the screening format and the high throughput speaks rather for the single compound approach. Once one or several hits have been identified, focused libraries incorporating structural features around these hits can be planned and synthesised. Parallel and combinatorial chemistry approaches are especially valuable tools in this phase of lead discovery as they speed up the validation and identification process of potential hits and leads. If high throughput screens are available single compound collections will be the favourite choice.

107


1.8.3. Parallel and split-mixed synthesis Reactions in solution or on solid supports can be carded out in a parallel format as schematically shown in Figure 1.8.3.1, where the two reactive building blocks RBA 1 and RBA 2 are reacted with building blocks RBB 1 and RBB 2 in four different vessels giving rise to the first generation of four intermediate products which are combined with RBC 1 and RBC 2 to give the eight possible products in eight different reaction vessels. This protocol allows to unambiguously identify every product in each reaction vessel but requires all manipulations for each reaction. Efficient parallel processing and automation of the time consuming steps such as washing procedures is a prerequisite in this approach. In the parallel approach RBA ~ and RBA 2 can also be reacted with a mixture of building blocks RBB 1 and RBB 2 giving rise to two mixtures of two compounds. Each mixture would further react with building blocks RBC 1 and RBC 2 in two separate vessels to give two mixtures of four compounds as indicated in Figure 1.8.3.2. A major problem associated with the synthesis of mixtures is that not all the reaction partners will couple with the same reaction rate and this will give rise to a non-equimolar distribution of the products. This problem could be solved more or less efficiently in the field of peptide 364,365 and oligonucleotide chemistry366 by adjusting the concentrations of the amino acid- and nucleic acid components according to their respective reaction rates. In the field of combinatorial synthesis of small molecules this problem is much more severe. Using the "split-mixed" or the "split and combine" technology developed by Furka et a/., 15,367

Lam eta/. 368 and Houghten eta/. 369 the problems of different reaction rates can be elegantly avoided as depicted schematically in Figure 1.8.3.3. The polymer-bound reactive building blocks RBA 1 and RBA 2 are in the first step mixed and then redivided in two equal portions of beads (RBA 1 and RBA 2 are represented in roughly equimolar distribution) which are then reacted individually with building blocks RBB ~ and RBB 2 to yield two pools (A ~ and B 1) of beads. As only one building block is coupled to one pool of beads large excesses of reagents can be used. Since the two pools contain a mixture of two product beads the product identification has to be performed either by cleavage of the products and analysis by mass spectrometry or by deconvolution or tagging techniques (see Chapter 1.10). The two pools A ~ and B 1 are mixed, redivided and further individually coupled with building blocks RBC 1 and R B C 2 to give two pools (A s and B 2) of beads containing four products each. Using this technology, all eight products can be generated with only four reactions compared to twelve individual reactions necessary in parallel approach (Figure 1.8.3.1).

108

Figure 1.8.3.1

,..,.

c~

,..,~

,,...,

8 products in 8 different reaction vessels

,..,.

Figure 1.8.3.2.

3"

r

2 mixtures of 4 products in 2 separate reaction vessels

o5


111


Advantages of the split-mixed methodology The split-mixed methodology is ideal for linear stategies like the synthesis of polypeptide libraries where the economisation of reaction steps gains importance. Large libraries can be synthesised, every bead containing only one single compound. Tagging or deconvolution are usually required in order to determine the structure of active compounds. The substances can be either tested on bead or after cleavage depending on the availability of biological tests. The methodology is limited, however, to relatively little material available on a single bead. Furthermore, resynthesis of the interesting members of the library in greater amounts will be necessary.

1.8.4. Linear versus convergent strategies In Chapters 1.8.1-1.8.3 we discussed the fundamental strategies of parallel and combinatorial synthesis. Whether reactions should be performed in solution or on solid supports or whether the compounds are obtained as singles or as mixtures from parallel or split-mixed synthesis, depends largely on the complexity of the underlying chemistry and the way compounds are identified and screened. The resulting structural diversity, however, is only determined by the way the molecules were assembled and the types of building blocks employed. The basic idea of combinatorial chemistry is to synthesise (starting e.g. from building blocks A, B, C ~, C 2, and C 3) all possible combinations of products (pl_p3, etc. (Figure 1.8.4.1)) either as single compounds or as mixtures. Since products pl_p3 were created from similar building blocks using the same chemical strategy, they form an ensemble or a library of compounds having the same core structure with all possible combinations of appended substituents. Prerequisites for a successful combinatorial approach are sets of highly reactive building blocks of type A, B, and C which can be readily assembled in a linear or in a convergent fashion (Figure 1.8.4.1).

112

1.8. Syntheticstrategiesin combinatorialand parallel synthesis

Figure 1.8.4.1

Linear assembly In a linear assembly strategy (see also Figure 1.3.2, Chapter 1.3) building blocks of one single type, e.g. A, are combined using usually a well established bond forming reaction, e.g. amide bonds for peptides, phosphorester bonds for oligonucleotides and glycosidic linkage for oligosaccharides. Assembly of A1-A3 readily gives access to 6 possible combinations (assuming that for steric reasons not all three substituents can be adjacent to each other (Figure 1.8.4.1, upper par0. Not surprisingly, combinatorial chemistry originated from linear assembly strategies developed in peptide and oligonucleotide chemistry (cf. Chapter 2), since both building blocks and coupling chemistry have been extensively studied in solution as well as on solid support.

Convergent assembly In a convergent assembly strategy the building blocks A, B, and C1-C 3 ultimately can form products p1p3. As can be seen from the simple sketch in Figure 1.8.4.1 (lower part) the core structure differs significantly from linear strategies. A convergent strategy is usually more demanding both in terms of having access to the reactive building blocks A, B, C1-C 3 ("reactophores") as well as elaborating the corresponding assembly chemistry. The whole plethora of organic reactions, e.g. condensation and pericyclic reactions, will be included. As will be

113

1. Introduction,basic conceptsand strategies discussed in Chapter 1.8.5 and 1.8.6, an exciting aspect of convergent strategies lies in the fact that building blocks A, B, and C~-C 3 can potentially be assembled in different ways (see Figures

1.8.5.1 and 1.8.5.2). There is currently a significant shift observable from linear to convergent strategies as mentioned in

Chapter 1.1, probably due to the fact that convergent approaches are more likely than linear ones to generate small "drug-like" molecules.

1.8.5. Multicomponent and multigeneration reactions When looking at multicomponent reactions we have to differentiate between multicomponent one-

pot reactions, where the reactive components react to a product without giving rise to isolable intermediates, and multigeneration reactions, where the reactions proceed via intermediates which can be trapped and isolated. The two reaction schemes differ significantly in their scope and application for combinatorial organic synthesis as schematically depicted in Figures 1.8.5.1 and 1.8.5.2. Lets suppose a case where polymer-supported reactive building block PS-A reacts with components B and C1-C3. A multicomponent one-pot reaction will always generate three polymerbound products PS-P 1 to PS-P 3 and after cleavage three final products P1 to p3 irrespective of the

sequence of addition of the reagents (Figures 1.8.5.1 and 1.8.5.2 upper half). Conversely, in the multigeneration version the sequence of mixing the components is important and consequently we have to distinguish between two possible cases as shown in Figure 1.8.5.1 (strategy A, lower half) and Figure 1.8.5.2 (strategy B, lower half). In strategy A, the polymer-bound reagent PS-A reacts first with building block B to generate the stable intermediate PS-P 4, which can either be cleaved to give 1st generation products p4 and/or be reacted with CI-C 3 giving rise after cleavage to the products pl_p3 (2nd generation). In strategy B, PS-A is first reacted with building blocks C~-C 3 to generate the stable intermediates PS-P 4 to PS-P 6, which can be cleaved to give 1st generation products p4_p6 and/or be reacted with B to generate after cleavage from the resin again products pl_p3. It is important to note that the multicomponent one-pot reaction always generates pl_p3 whereas in strategy A (Figure 1.8.5.1) of the multicomponent cascade version four products pl_p4 with two different core structures are formed while in strategy B (Figure 1.8.5.2) six products pl_p6 with two different core structures are generated. This simple sketch already illustrates the implications of multicomponent one-pot and multigeneration reactions on the number and on the diversity of the products that can be generated. While one-pot reactions allow the parallel generation of products with a minimum amount of manipulations and vessel transfers, the multigeneration versions offer the benefit of having access to a larger number of compounds and core structures, which ultimately results in greater diversity of the produced compound collections. In Chapter 1.8.5.1 we will describe some of the most

114


important multicomponent one-pot reactions, while in Chapter 1.8.5.2 we will discuss some aspects of multigeneration reactions.

L.

o i...

o o o c 0 "ID Jo o "0 0 Q. i_

0

< o.

>,

L_

0rj

t6

115

c~

Figure 1.8.5.2

r~

Strategy B: six compounds based on two core structures


1.8.5.1. Multicomponent one-pot reactions The pioneer of multicomponent reactions and one of the first scientists to extend multicomponent reactions to the generation of compound libraries was certainly Ivar Ugi. The two classical four component reactions combining an acid (R1COOH, 1), an aldehyde (R2CHO, 2), a primary amine (R3NH2, 3) or a secondary amine (R3RaNH, 5) and an isonitrile (R4NC or RsNC, 4) are described in Schemes 1.8.5.1 and 1.8.5.2, respectively.

Scheme 1.8.5.1

O R1-COOH 1

+ R2-CHO

+

R3-NH2 +

2

R4.N=C

3

4+

R1"

4

N-R4 5

O

R

Mechanism:

R2

O,~ R1

-O)

f~ H +

(.

~-,,,~N- R3

N , ~ ~ ' N H R3 H+

Scheme 1.8.5.2.

RI-COOH 1

+ R2-CHO

+

R3R4NH + RS-N=C

2

5

O•.R

1

Mechanism"

R -N-C-

O

4

O

R3

I

6

R1

"~ O1~O ti~

N

R3 I

N. R4

As typical for multicomponent one-pot reactions, the four components have potentially many possibilities to react in one way or another and many reversible equilibria will co-exist in the reaction mixture. After formation of the imine or immonium species which is still a reversible process, reaction of the isonitrile and the carboxylate with the imine generates a reactive acyloxyimine, which in the case of a primary amine 3 can rearrange to form a N-alkylated dipeptide 5

117


(Scheme 1.8.5.1) or, in the case of a secondary amine 5, can rearrange to give imide 6. Both products constitute the thermodynamically most stable species in the reaction mixture. Many variations of the Ugi four component condensation (Ugi-4CC) have been published and a short compilation is depicted in Figure 1.8.5.3.

Figure 1.8.5.3 OH

O R4

0

0

0

Rs

RIc02H

R2 R3 R4

~X

~

R3COR4 RSF:PNH

a~

N

R7

RL~,, N.,R~

-'

R2 R5 R4

H

R2COR 3 R4NC

NH20H

R1CO~I R2NC

R2 N" R30 R

N"

R10021..I R2R3NNH2 /

R6

H

R4CORs, R6NC

\

R~I:~NH,R3NC

Ugi-4CC

R4CORs, RSRTNH

R~NC R2COI=P R4RSNH,HN3

H ~/~adation

R1

R~3OR4, R%C ~R

RIR2NH / R3COR4 / _ -sNC / 3CC-

R2 O ~ .,g,~ Rs "K N" " ~O R3 R4 H

R1CO2H,R2NH2

1NC,R2COI:P " ~ N H 2 , RsNCX

" , ~

R4

R3

R5

,N-.. N

R3 R4 I~~

g,

R4 RS

Related to the Ugi reaction is the Passerini three component variation 37~ as shown in Scheme 1.8.5.3.

Scheme 1.8.5.3 o

RI-COOH

+ R2-JJ',.R3

+

+

-

R4--N-C

o

H

_- R1JJ,,.o~N,R 4 0

Several variations in which two of the functional groups are attached in the same molecule have been successfully used to synthesise anellated heterocyclic ring systems. Several interesting applications will be shown in Chapter 3.3.

118


In Scheme 1.8.5.4, three versions of the Hantzsch multicomponent one-pot reaction are shown leading to thiazoles, pyrroles and dihydropyridines. 371 Scheme 1.8.5.4 thiazoles:

X

R3

+ R1ANH2

~ R2

O

R2

R1

X

R[ N

NH2

H

R2

R3 HN ~1

O

R2

S

(X = CI, Br)

pyrroles: O R 1. ~ C O O R i

i

i

2

+

NH3 +

tCOOR2

O R3J~x i

R3

R1 H

(X = CI, Br) dihyd ropyridines: O R1

COOR 2 +

NH3 +

R3-CHO

=R Z ~ ) ~ O R 2 R 1"~ N ~ H

R1

One of the oldest multicomponent reactions is certainly the Strecker-synthesis,372, 373 in which an aldehyde is condensed with ammonia and HCN to form an aminonitrile as shown in Scheme 1.8.5.5 (entry a). Scheme 1.8.5.5

a:

b:

R-CHO

+

NH2

.Ac.

NH3 + HCN

O R IJ~'-'R 2 + KCN

0 +

(NH4)2CO3

=

HN

o)/-..

R2

119


As many of the classical multicomponent reactions, the Strecker synthesis also takes advantage of the versatile chemistry of the initially formed imine. The formation of the amino nitrile, however, is reversible under the reaction conditions which usually results in lower yields. This problem was elegantly solved in the Bucherer-Bergs variation, 374-376 where the initially formed aminonitrile is irreversibly trapped by formation of a hydantoin as depicted in Scheme 1.8.5.5 (entry b).

The Mannich reaction 377 (Scheme 1.8.5.6) involved in the biosynthesis of many alkaloids (e.g. tropane alkaloids, gramine) has been synthetically used in many elegant syntheses of alkaloids such as porantherine. 378

Scheme 1.8.5.6

R

H R2 + CH20 + I~N.

.j,,..jj.R 4 O R3 v ~ R5

= R3 R

R5

R1 !

H RlfN. R2

~ + CH20 +

~ H

N'R2

=

H

The Erlenmeyer azlactone synthesis (Scheme 1.8.5.7) combining a hippuric acid derivative, acetic anhydride and an aldehyde to form a didehydroazlactone. This azlactone approach has been extensively used for the synthesis of amino acids. 359

Scheme 1.8.5.7

O RI,JJ'-NACOOH + Ac20 + R2-CHO H

a2

NaOAc R1

O

The Biginelli reaction 379,38~combines ureas with an aldehyde and a [3-oxoacid derivative to form dehydropyrimidones as shown in Scheme 1.8.5.8.

120


Scheme 1.8.5.8

O

HN,~CO2R3

O

H2N.,~NH2 +

RI-CHO + R2J~ COOR3

H The Atwal modification of the Hantzsch synthesis consists of a condensation reaction between a

thiouronium salt, an aldehyde and a [3-oxoacid derivative to form dihydropyrimidine derivatives 13 as shown in Scheme 1.8.5.9. Scheme 1.8.5.9

NH O SJ~ ' + R2-CHO +R3~COOR4 R1 NH2

a2

N,~CO2R4

R'. JL.. L S

N

H

R3

An interesting variation of the classical multicomponent reaction was recently described starting from a glyoxale and a tetrahydroisoquinoline generating in the first step an immonium species which underwent 1,3-dipolar cycloaddition with N-methyl maleimide as shown in Scheme 1.8.5.10. 381

Scheme 1.8.5.10. o

R1

CHO

+

H, ,, ~ - - , , , , , , ~ -

+

- R1 O

O~"- N/'~O I

Combining a glyoxale, 2-(phenylthio)acetic acid and an isonitrile gave, in a modification of the Passerini reaction, substituted oxazoles 382 as depicted in Scheme 1.8.5.11. Scheme 1.8.5.11.

O R,ACHO

+ R2-NC +

ph~SvCOO H NH4+HCO3 R ~ ~ O "R2.NH N.~sPh

121


A novel three component reaction developed by Hogan and coworkers 383 involves condensation of esters, substituted hydrazines and epoxides to yield hydrazide derivatives as shown in Scheme 1.8.5.12. Scheme 1.8.5.12 O

R2

R1/IL"OR

O

R4

R3

O

R2 ,R3 OH

R1

R4

An interesting novel, Lewis acid catalysed three (or four) component reaction between a silyl enol ether, an enone and an imine leading to ~-lactams was recently reported by Kobayashi et al. 384 Scheme 1.8.5.13

R3

Lewis

OSiMe3 O RIx~rR2 + R 3 ~ R 4 + R5~N.Rs

acid

"

R202 R~6

O

RsR4

The Pauson-Khand reaction combines efficiently an alkyne, an alkene and carbon monoxide to

form cyclopentenones (Scheme 1.8.5.14) and belongs to the very few purely C-C-coupling based multicomponent reactions. 385 Scheme 1.8.5.14

R1 ~

R2

+

R3 ~

R4

+

O R~4~R Rs

CO

An interesting three component reaction combining anilines, olefins and aldehydes forming tetrahydroquinolines was described by Grieco et al. 386 and applied by Armstrong et al. for the construction of libraries based on this core structure387is presented in Scheme 1.8.5.15. Scheme 1.8.5.15

COOH

NH2

122

CHO

+o+6

TFA (I

COOH H

eq)

MeCN

:H

0


1.8.5.2. Multigeneration reactions The following examples illustrate the important differences between multicomponent one-pot reactions and multigeneration reactions. Many of the previously mentioned multicomponent onepot reactions proceeded via intermediately formed imines. Instead of forming these imines in situ they can be synthesised separately and engaged in a whole range of reactions as schematically shown in Scheme 1.8.5.16. The utility of carrying out the reactions in a multigeneration mode is obvious. The number of accessible products and core structures increases substantially.

Scheme 1.8.5.16

R2

Rt N .,1. Ro NaCNB

H

H3~

O R1--NH2

(R 1=aryl R3=H) R2

+ R2JJ"Ra

=

~/

R4

R H

(R =CH2R)

R 1 N ~ R3

OSiMe3

R5A~''COOEt

Ugi reaction R i

i

R7

O/~"N"J" R2 I~11

R3 R2

R3 R2 jj,,, N~,~I~ NH a 9 Rl~ I i~ R1 0

R5 O

....R H

Indeed, most reaction sequences can be regarded as multigeneration reactions in which every reaction step generates a reactive species ready to undergo the next transformation. The perfection of this concept axe the so-called "tandem"-, "domino"- or "cascade"-reactions in which the intermediates undergo the next transformation directly, i.e. without isolation or activation. Two examples will be discussed below to illustrate this concept.

123


Blechert et al. 388 developed a multicomponent cascade reaction for the synthesis of indole

derivatives as depicted in Scheme 1.8.5.17. The first step of the sequence involves formation of a nitrone derivative starting from phenylhydroxylamines and aldehydes. The resulting nitrones were not isolated but captured by a cyanoallene in a 1,3-dipolar cycloaddition reaction followed by hetero-Cope rearrangement, ring-opening and condensation to yield an indole derivative.

Scheme 1.8.5.17

1)

R 1-CHO

R3

R2 ~

= NHOH

_

R3 2) X = C ~ c

N

// R2

H

J

R3

IL

CN

NH!

R1

R 2 ~

R3 RI~cN

R3

=

CN

R2 H

R'

Variation of the different building blocks allowed subsequent anellation reactions. A broad range of indole alkaloid derivatives were generated using this strategy as shown in Figure 1.8.5.4.

124

1.8. Syntheticstrategies in combinatorialand parallel synthesis

Figure 1.8.5.4

CN H

H

d

~ N

"\

H

tk,,,,~'~ N" H

~

CN

"CN

R1

H

~ N

H

O

C

N H

R2

~a

/

The tandem reaction studied by Neier et al. 389-391 is a combination of a Diels-Alder process and a Ireland-Claisen rearrangement. These pericyclic reactions usually proceed with good regio- and

diastereoselectivities. In addition, the mechanisms of both reaction types are well known. Thus, Obutadienyl-O-TBDMS ketene acetals la-e react with electron-deficient dienophiles such as Nphenylmaleimide at 60~ to yield initial Diels-Alder products rac-2a.e. These products are not isolated, but the newly created double bond in the cyclohexene moiety participates instantanously in an Ireland-Claisen-type rearrangement to form the substituted cyclohexenes rac-3a-e as single diastereoisomers. The products rac-5a-e were isolated after hydrolysis of the silyl ester and estedfication with TMS-diazomethane in 43-77% yield (Scheme 1.8.5.18).

The relative

configuration of the products was controlled by the geometry of the starting ketene acetal 1, the endo-selectivity of the Diels-Alder reaction, the facial selectivity of the sigmatropic rearrangement involving a boat-shaped transition state and was confirmed by an X-ray crystal structure determination of 4e.

125


Scheme 1.8.5.18

~OTBDMS a

O'eR,

I-

OTBDMS

7

la-e

O

/

i ) . 1 ~ ~ ~

TBDMSO" ~.. v R' R

rac-2a.e

~'~ 0

rac-3a.e

l ii)

O MeOROR, '~~oO

N-C6H5

0 iii)

0 ~ O ' HO

rac-Sa-e

N - C6H5

rac-4a.e

5a: R, R'= H, H (70%) 5b: R, R'= CH3, H (77%) 5r R, R'= CH3, CH3 (56%) 5d: R, R'= OCH3,H (75%) 5e: R, R'= Phthalimido,H (65%) Reagents and conditions: i) N-phenylmaleimide,THF, 60~

r.t.; ii) 25% H2SiFs,DME, 30 min r.t.; iii) TMSCHN2,THF,CH3OH,2h, r.t.

The cyclohexenes 5a-e obtained from the tandem Diels-Alder reaction / Ireland-Claisen rearrangement sequence represent interesting building blocks with well defined geometry which are not easily accessible using other routes.

126

1.9. Classification of reactive building blocks

1.9. Classification of reactive building blocks Despite the fact that more effort has to be put into the synthesis of suitable building blocks, we focus mainly on convergent strategies, which will lead more likely than linear strategies to smallmolecular-weight "drug-like" molecules. Figures 1.9.1

and 1.9.2

schematically show the

construction of a library of molecules on solid support using a convergent multigeneration and a combined

multigeneration/multicomponent

approach

coupled

with

monofunctional

or

multidirectional cleavage. The first step usually involves coupling of a reactive building block RB 1 ("reactophor 1") via a linker molecule to a solid support. A reactophor is a reactive building block that consists essentially only of a reactive group and appended orthogonally protected functional groups which will serve as points for diversification. As previously discussed, the choice of the linker group is of prime importance as it determines the scope and limitations of the chemistry that can be employed to synthesise the compounds. Building block RBI consists of a reactive part that serves to construct the core structure of the target molecule, of one or several appended orthogonally protected functional groups G 1 and of an attachment site for a suitable linker group. The core structure, which will be most likely an interesting pharmacophor, is assembled by the reaction of RB 1 with RB2, which also contains orthogonally protected functional groups G 2 and G 3. Groups G1-G3 can now be converted into the final modified groups A, B, and C employing I building blocks of type A, m of type B and n of type C (Figure 1.9.1). In all these reactions the actual library is formed either as single compounds when the reactions are all carried out in separate vessels, or as mixtures when all reagents A(/), B(m) and C(n) are added at the same time to a suitably activated functional group. In Figure 1.9.2 the modification of G 3 occurs by means of a multicomponent reaction (polymer- bound molecule + components C, D and E) leading to the generation of I x m x n I x n 2 x n 3 polymer-bound molecules.

This sketch emphasises again the importance of using multicomponent reactions in the diversification steps. Once the library is formed on the solid support, the molecules can be cleaved either by liberating one functional group or in a multidirectional mode. Note again, that the latter case generates o analogues of the built library in the final step.

127


Figure 1.9.1. Convergentmultigenerationassembly strategies

128


Figure 1.9.2. Convergentmultigeneration/multicomponentassembly strategy

129


The important features of such an approach can be summarised as follows: 9 The careful selection of the reactive building blocks ("reactophores") is a key issue as they predetermine the core structure and the appended functional groups. Orthogonally protected functional groups minimise the number of chemical transformations on the solid support and thus will increase the overall yield. 9 In the actual diversification phase it is useful to incorporate multicomponent reactions for creating a large set of core structure analogues in a given step. 9 Multidirectional cleavage reactions also amplify the number and the actual diversity of the synthesised compound library as shown in Figures 1.9.1 and 1.9.2. 9 It was our aim to extract from the literature and from our own work the prototypical reactive building blocks that are especially well suited for such a multigeneration/multicomponent approach. We have classified the reactophores into three categories: 9 mono-, bis- and polydentate donor molecules (Chapter 1.9.1) 9 mono-, bis-, tris- and polyacceptor molecules (Chapter 1.9.2) 9 acceptor-donor molecules (Chapter 1.9.3)

The goals of classification: In the initial phase the classification of reactophores was just an excercise to get an overview about the type of building blocks which were employed in solid-phase reactions. A careful analysis of those building blocks and reactions revealed that essentially all of them could be grouped into the above mentioned categories. In a second study we analysed the building blocks that were used in multicomponent one-pot reactions. Again, most of them fell into one of those categories. We were especially interested in reactive building blocks that would allow to carry out multicomponent-cascade reactions giving rise to different core structures depending on the sequence of mixing ("combinatorics of building blocks"). Ultimately, this excercise can lead into the discovery of novel multicomponent reactions.

130

1.9. Classificationof reactive building blocks

Requirements to a reactophore for COS 9 Reactive and yet still storable at -20~ 9 Should be synthesisable in gram quantities 9 A convergent synthesis should be available that allows for an easy introduction of a wide range of orthogonally protected functional groups 9 Each reactophor should lead into different core structures, depending on the reactive counterpart and the sequence of mixing. 9 Orthogonally protected functional groups should allow a quick and easy diversification phase.

1.9.1. Mono- and polyvalent donor building blocks (nucleophiles) In Chart 1 are listed the most frequently employed mono-donor building blocks in SPOS such as

tertiary amines, phosphines, phosphites, alcohols, boronic acids,

stannanes,

acetylenes,

carboxylates and various organometallic nucleophiles. These building blocks are mostly used for the diversification steps to "decorate" the previously constructed core structures (see Figures 1.9.1 and 1.9.2) or for the final cleavage reactions. In Chart 2 are depicted various poly-valent donor building blocks such as thiols, secondary amines, phosphoryl imines and ylids which serve both the purposes of diversification and cleavage as well as of construction of the central core structures. Bidentate nucleophiles such as thioamides, thioureas, ureas, isothioureas, amidines, guanidines, 1,2-dihydroxybenzenes, 2-aminothiophenols and others (see Chart 2) were exclusively employed for the synthesis of the cores as exemplified in Chapter 3 and 4 (the indicated references refer to these examples)

131


Chart 1: Monodentate donors

R1/N2R3

1

392

R

RI~P" R3 R2

O R~O-Cs + O

2

N-K +

O S

10

359, 393

RI--Zn--R 2

11

331

R-Li

12

RI,,~NR2R 3

R-OH ~

4

B(OH)2

19, 394, 395

5,354

F', soR3

396-399

R-MgX

13

344, 400, 401

14

404

R R

7

394, 402, 403

R

,CuLi

R

132


Chart 2" Polydentate donors

R-SH

61, 394, 405

~

SH NHR2

R1 H RlIN-R 2

I

i

R1 N=pR23

RO-NH2

12

RI,,~NH2

13

60, 61, 344, 364, 397, 4o6-412

359, 406, 407, 409

aI

R2/~NH 2 N"

4, 413, 414

~pR23

II

OH

14

393

R.,'~ NH2 R~

NH

R3

N--N

R:~

S RI-"~ NHR2

16

I I

R1R2N.,.,~ NH2

S

R1R2N~

H

NH

359, 393

H

15

R~NHNH2

'R4

NR2R3

359

NR3R4

~NR4R N1

17

359, 415

18

359

19

359

5

O

R1R2N,,'J~ NR3R4

R

~

~

R1

OH

4, 344

OH OH

~

R 10

SH NH2

H RI~ P~.R2

20

NHR2

133


1.9.2. Mono- and polyvalent acceptor molecules (electrophiles) In Chart 3 are shown first the mono-valent acceptor building blocks such as alkyl and aryl halides. These electrophiles are exclusively employed in the diversification steps or as final "scavenging" or "capping" reagents in cascade reactions. Acceptor molecules derived from aldehydes ketones, oximes, carboxylic acids and amides, nitriles, nitrones and others are used for both derivatisation reactions and the construction of central core structures. Bidentate acceptor reactophores such as o~bromoketones, o~,[5-unsaturated ketones and derivatives, glyoxals and o~-alkynyl ketones (cf. Chapter 1.9.4) are the prototypes of key building blocks useful for SPOS as they allow the

synthesis of a whole range of heterocyclic core structures. Some of the most interesting examples will be shown in Chapters 3 and 4. Chart 3: Mono- and polyvalent acceptor molecules

~

X

X

= Br,

1394, 396, 402, 403, 407, 416

X = OTf 331, 417

R

X = OMs 4,5

RmX

N_Alkylation60, 95, 344, 364, 397, 406-409, 411,412 C_Alkylation272, 354 S_Alkylation61, 394, 405 O_Alkylation19, 45, 394, 395, 418-420

O

Acetalisation421, 422

RAH

Imine formation 344, 411,423-427 Wittig reaction 413 Horner-Emmons reaction 414

Nitro-aldol reaction 428, 429

RI,~R 2 O

wLc, 0

oA N"

OH

Ac,

134

c,

401

95, 311, 344, 398, 399

430, 431

~432


Chart 3: Mono- and polyvalent acceptor molecules (continued)

R-C-N

RI,~OR2 O

10

344

11

359, 393

O Br',,,,,~CI

12

433

O B r ' , v ~ NR1R2

13

61, 406, 407, 409

14

344

15

434, 435

16

436

17

437

24

29, 344, 438-441

25

442

EtO'J~OEt

Br~. R2 R1

Ro

oR

O

O

R•H O

R~OR2 0

O

CHO

Br---~

CHO

O RI~JJ~OR 2 O~-,,~R3

o~o a2

Rl"j~

26

O

135


Chart 3: Mono- and polyvalent acceptor molecules (continued)

R

O

ON

27

MeS~] SMe NO... ON

28

443

29

98, 359, 444

MeS'~SMe a2

RI.C-C-~ O

Br ~

R

30

0

1.9.3. Acceptor-donor

molecules

Combining nucleophilic and electrophilic centers, acceptor-donor molecules are highly versatile building blocks useful in many multicomponent and multigeneration strategies. After initial reaction with a donor molecule, these building blocks can potentially generate a novel donor center ready for reaction with a further acceptor-donor building block in a chain reaction or react with an acceptor species to terminate the cascade. In Chart 4 are listed some of the most popular and useful acceptor-donor reactophores that have been used in combinatorial and parallel synthesis such as epoxides, episulfides, imines, 13diketones. 2,2-Disubstituted 3-amino-2H-azirines constitute a highly reactive class of acceptordonor reactophores that have been shown to be useful for the generation of a range of diverse heterocycles under mild reaction conditions. Furthermore, isocyanates, isothiocyanates and carbodiimides belong to the class of prototypical acceptor-donor reactophores as they exhibit high reactivity and are readily available.

136


Chart 4: Acceptor-donor molecules R

o

344, 383

O

13

359, 412

R

a2 N.~.-- R3

S

14

R,--4o, O

a1

445

O HS?oR2

15

422, 424, 444, 446

O O R1 " ~ R2

16

344, 438, 440, 448-

O O RI.~',V~OR2

17

N

a1

99,

k=--N

"R2

428, 452

R

k=--C=o

R

455

N=C=O

344,

O NCv,'[L.OR

4 2 7 , 455-

461

463

CN NH2

O

451

54, 393, 441, 448, 451, 453

18

437

19

344, 455

20

344, 413, 462

R 1 0 ~ ~ R 3 OR2

R.O R

O

454

N=C=S

~

411,

423-427, 447

R-C_-__N-O

R

344,

10

464, 465

O R1~ , , ~ , ~ R 2

O R1OA~"~OR2 O

RI~R Br

2

21

22

137

1. Introduction, basic conceptsand strategies Chart 4: Acceptor-donor molecules (continued) O

~.JL/.,~_NH~Me R O

11

O

432

23

407

24

359

NHR Br

12

407

R1-N=C=N-R 2

R

1.9.4. Acetylenic ketones as typical representatives of a bis-acceptor reactophore As defined earlier, reactive building blocks that are useful for solid supported combinatorial and parallel approaches show a high reactivity, allowing the synthesis of several different core structures by muticomponent one-pot and multigeneration reactions. In addition they should be storable at -20~ and synthesisable in reasonable quantities (several grams) containing orthogonally protected functional groups for subsequent introduction of further elements of diversity. A classification of these reactive building blocks was presented in Chapters 1.9.1-1.9.3. An excellent example for such a class of reactive blocks constitute the a-alkynyl ketones (acetylenic ketones) as typical representatives of bis-acceptor molecules. They show the following features: 9 a-Alkynyl ketones are formally analogues of [3-dicarbonyl compounds 9 In contrast to [3-dicarbonyl compounds a-alkynyl ketones show good to excellent regioselectivities in the reaction with bidentate nucleophiles such as 2-amino thiophenols 466 and hydrazines (Scheme 1.9.4.2) 9 They are synthetically easily available by simple acetylenic C,C-coupling reactions (Scheme

1.9.4.1) 9 They tolerate a wide range of functional groups (Scheme 1.9.4.1) 9 They react with mono- and bidentate nucleophiles to yield a wide range of mono- and bicyclic heterocycles (Scheme 1.9.4.2) 9 They show a good balance between reactivity and stability (storage at 0~ possible) 9 They can be easily synthesised on gram scale with a large variety of orthogonally protected functional groups.

138


a-Alkynyl ketones are readily available by the reaction of a lithium or magnesium acetylide with either an aldehyde followed by subsequent oxidation with MNO2.467-469 or by reaction with a Weinreb type amide47~ followed by hydrolysis as shown in Scheme 1.9.4.1. Scheme 1.9.4.1

R1-H1

i),i),ii)i),O"riv) II ~R ~ R1

Rl: H, alkyl, aryl, SiMe3, Br, CH2OTHP, CH2NHBoc, CH2NHZ, CH2NHTs CH2NBoc2, CH(OEt)2, COOMe, COOtBu, SO2Ph, CN, SnBu3, CH2C(Me)2OH R2: H, alkyl, aryl, heteroaryl, CH2OTHP, CH2NHBoc,CH2NHZ, COOEt Reagents and conditions: i) iPrMgCI or nBuLi, THF, -78~

ii)R2-CHO; iii)MnO2;iv) R2CON(OCHa)CHa,HaO§

In Scheme 1.9.4.2 are depicted some applications of ct-alkynyl ketones in order to demonstrate

their scope and utility for COS. Thus, acid catalysed isomerisation reaction of acetylenic acetals 3 yield the pharmacologically interesting (E)-4-oxobut-2-enoic acids 4 in high yields47~ (entry a). Acetylenic ketones 5, 9 and 13 or acetals 8, 12 and 16 gave by treatment with HBr in a regioselective manner 3-halofurans 6 and 7469 (entry b), 3-bromothiophenes 10 and 11467 (entry c), and N-protected bromopyrroles 14 and 15 468 (entry d). These building blocks can be further functionalised, e.g. they have been used for the synthesis of optically pure amino acid analogues. 359 Treatment of acetylenic ketones 2 with methyl thioglycolate gave in a tandem Michael-addition~ intramolecular Knoevenagel-condensation highly substituted thiophenes 18 in high yields444 (entry e). 2,4-Disubstituted quinolines of type 21 were obtained from acetylenic ketones 2 as a result of a condensation reaction with 2-amino thiophenol 19 followed by sulfur extrusion466 (entry f). Acetylenic ketones have also been employed as dienophiles in Carbonyl-Alkyne-Exchange (CAE) reactions with dienes 22 (derived from 2,2-dialkyl-2,3-dihydro-4H-pyran-4-onesn71)(entry g) or 24472 (entry h) to yield aromatic compounds 23 and 25 in a highly regioselective way. 139


Reaction of 2 with alkyl- and arylhydrazines gave varying amounts of pyrazoles 27 and 28 359,473 (entry i). Acetylenic ketones 29 cyclised upon treatment with HBr to give flavones 30469 (entry k). Amino acid derivatives 32474,475 and 34476 were obtained by reaction with acetylenic ketones 3 1 and 33 (entries 1 and m). S c h e m e 1.9.4.2

O J ~ R1 3

OEt

4N aq. HBr toluene =

4

Br

HBr

b)

O

R1 R2

oIIl

R I ~

R1

HBr EtO

7

Br

HBr

HO.. R1

Br

6

5

TrS,.

COOH

OEt

a2

HO

R1

TrS..

Br 2

~ R

10

OEt 8

HBr 1

11

Et

12

9

RHN.

R2 HBr

d) 0

R1

Br

BF

R1"~2 i

R 15

R14

13

RHN. HBr

R1

EtO" "OEt 16

R= Boc, Z, Ts a1

HS A C O O M e

140

OEt

I~

a2

2

R1

R1

17

0s2003 =-

R2~COOMe 18


Scheme 1.9.4.2 (continued)

R2 O

'i

[~ R1

2

SH NH2

1

19

2

a2

R5

OR 5

R4

g)

R3

R

OI~R 1

21

2O

2

22

R2

SR5

R2

R4 R3

R2

O~R1 2

24

a2 i)

R2

~

+

0

R3NHNH2

RI~N.N

26

1

R2

+

RI~~N.N.~R3

50g ,...,.


Whereas the format, size and degree of automation vary considerably in these different workstations and robotic systems, the basic operations remain the same. Therefore, with the aid of a schematic representation of a medium sized workstation an illustration of the basic modes of action should be achieved (Figure 1.13). Figure 1.13

Legend: A

Reservoir to address solvents for washing cycles or for dilutions

B

Valve system controlling the addition of solvents and reagents Computer system handling the operation of the robotic arm D, valve system B, adressing of reagents and solvents. In addition, the data (structural and spatial) of the products synthesised in a parallel array is handled electronically (typically with ISIS Base or similar data base)

162

1.13. Robotic systems and workstations

D

Robotic ann containing several automatic syringes (typically 1-8) which address reagents or solvents (for dilution or washing cycles) to the reaction vessels. The robotic arm is programmed to move to reaction blocks E, G, I and K Reaction block containing reaction vessels (typically 8-96) suitable for solid-phase and solution chemistry. The reaction block (made from Teflon | or aluminium) can be vortexed as well as cooled and heated (typical temperature range -40 to 150~

F

Reservoir to collect solvents from washing cycles (waste)

G

Cleavage block

H

Compounds are collected in parallel array from cleavage block.

I

Block for liquid/liquid extractions in solution chemistry

K

Block containing reagents as normalised solutions or automatically weighed.

L

Solutions collected from cleavage block are evaporated in parallel and analysed by LC/MS.

163


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(547) C.-D. Chang, M. Waki, M. Ahmad, J. Meienhofer, E. O. Lundell and J. D. Huag, Int. J. Pept. Prot. Res. 1980, 15, 59. (548) J. Meienhofer, M. Waki, E. P. Heimer, T. J. Lambros, R. C. Kakofske and C.-D. Chang, Int. J. Pept. Prot. Res. 1979, 13, 35. (549) D. A. Campell and J. C. Bermak, J. Am. Chem. Soc. 1994, 116, 6039. (550) S. L. Beaucage and R. P. Iyer, Tetrahedron 1992, 48, 2223. (551) M. H. Caruthers, A. D. Barone, S. L. Beaucage, D. R. Dodds, E. F. Fisher, L. J. McBride, M. Matteucci, Z. Stabinsky and J.-Y. Tang, Meth. Enzymol. 1987, 154, 287. (552) G.-S. Lu, S. Mojsov, J. P. Tam and R. B. Merrifield, J. Org. Chem. 1981, 46, 3433. (553) G. C. Look, C. P. Holmes, J. P. Chinn and P. A. Gallop, J. Org. Chem. 1994, 59, 7588. (554) E. Giralt, J. Rizo and E. Pedroso, Tetrahedron 1984, 40, 4141. (555) W. Schoknecht, K. Albert, G. Jung and E. Bayer, Liebigs Ann. Chem. 1982, 1514. (556) E. Giralt, F. Albericio, F. Bardella, R. Eritja, M. Feliz, E. Pedroso, M. Pons and R. Rizo, in: Innovations and Perspectives in Solid Phase Synthesis, R. Epton (Ed.), p. 111, SPCC (UK) Ltd: Birmingham (1990). (557) M. M. Murphy, J. R. Schullek, E. M. Gordon and M. A. Gallop, J. Am. Chem. Soc. 1995, 117, 7029. (558) G. C. Look, M. M. Murphy, D. A. Campell and M. A. Gallop, Tetrahedron Lett. 1995, 36, 2937. (559) R. C. Anderson, J. P. Stokes and M. Shapiro, Tetrahedron Lett. 1995, 36, 5311. (560) R. C. Anderson, M. A. Jarema, M. J. Shapiro, J. P. Stokes and M. Ziliox, J. Org. Chem. 1995, 60, 2650. (561) W. L. Fitch, G. Detre, C. P. Holmes, J. N. Shoolery and P. A. Kiefer, J. Org. Chem. 1994, 59, 7955. (562) C. Dhalluin, C. Boutillon, A. Tartar and G. Lippens, J. Am. Chem. Soc. 1997, 119, 10494. (563) J. I. Crowley and H. Rapoport, J. Org. Chem. 1980, 45, 3215. (564) B. Yan, J. Org. Chem. 1995, 60, 5736. (565) D. W. Vidrine, Photoacoustic FT-IR spectroscopy of solids and liquids, in: FT-IR spectroscopy, (Ed.), chapter 4, p. 125, Academic press: New York (1982). (566) J. W. Metzger, K.-H. Wiesmuller, V. Gnau, J. Brunjes and G. Jung, Angew. Chem. Int. Ed. Engl. 1993, 32, 894. (567) J. W. Metzger, C. Kempter, K.-H. Wiesmtiller and G. Jung, Anal. Biochem. 1994, 219, 261. (568) R. S. Youngquist, G. R. Fuentes, M. P. Lacey and T. Keough, Rapid Commun. Mass Spectrom. 1994, 8, 77. (569) G. Jung and A. G. Beck-Sickinger, Angew. Chem. Int. Ed. Engl. 1992, 31,367.

183


(570) J. A. Boutin, P. Hennig, P. H. Lambert, B. S., L. Petit, J.-P. Mathieu, B. Serkiz, J. P. Volland and J.-L. Fauch~re, Anal. Biochem. 1996, 234, 126. (571) T. Carell, E. A. Wintner, A. J. Sutherland, J. Rebek, Y. M. Dunayevskiy and P. Vouros, Chem. Biol. 1995, 2, 171.

(572) Y. Dunayevskiy, P. Vouros, T. Carell, E. A. Wintner and J. Rebek, Jr., Anal. Chem. 1995, 67, 2906. (573) M. Stankova, O. Issakova, N. F. Sepetov, V. Krchnak, K. S. Lam and M. Lebl, Drug Dev. Res. 1994, 33, 146. (574) M. Karas, D. Bachmann, U. Bahr and F. Hillenkamp, Int. J. Mass Spectrom. Ion Proc. 1987, 78, 53. (575) M. Karas, U. Bahr and F. Hillenkamp, Int. J. Mass Spectrom. Ion Proc. 1989, 92, 231.

184

Chapter 2

Linear Assembly Strategies 2.1. Introduction In Chapter 1.8.4 we have analysed and compared linear and convergent approaches as the two basic strategies to assemble molecules in a rapid and efficient way. In Table 2.1, the most important building blocks used in linear strategies and products thereof are summarised.

Table 2.1

monomers

bond formation

polymers

amino acids

amide bond

peptides, proteins

nucleotides

phosphorester bond

oligonucleotides

mono- and disaccharides

glycosidic bond

polysaccharides

N-alkylated glycines

amide bond

peptoids

Linear strategies employ a readily available set of monomeric building blocks such as suitably protected amino acids, nucleotides, monosaccharides or N-alkylated glycines which can be assembled in a repetitive sequence of couplings to produce the corresponding products such as peptides, oligonucleotides, polysaccharides or peptoids. Most of these linear strategies are used by nature to produce the basic molecules of life such as proteins, DNA, RNA and polysaccharide derived natural products. Linear strategies in combinatorial synthesis have been extensively summarised and since the present work focuses more on convergent strategies for the synthesis of small molecules we will try in this chapter to summarise only the most important aspects of this very broad field.

185

2. Linear assemblystrategies

2.2. Peptides 2.2.1.

General

The syntheses of peptide libraries that have appeared in the literature so far can be divided into mainly three categories: 9 Libraries synthesised using a molecular biology approach on the surface of filamentous phage particles or plasmids. These phage display methods have found wide use in protein epitope mapping approaches of proteins and protein domains. Several reviews appeared in the literature summafising the work in this field. 1-3 9 Peptides synthesised as individuals or mixtures on solid supports such as resin beads derived from polystyrene, polyacrylamide, polyacrylamide/polystyrene co-polymers (cf. Chapter 1.5) and cleaved to be assayed in solution. 9 Peptides synthesised and assayed as individuals or mixtures on solid supports such as pins, 4 resin beads, 5 cotton, 6 the silicon surface of microchips 7 or cellulose membranes. 8

Mixtures of peptides can be obtained using two different strategies:

a)

as true mixtures where a peptide coupling step involves the coupling of a mixture (typically the 20 coding amino acids) of side-chain protected Boc- or Fmoc-amino acids (L- or Disomers) in a predetermined molar ratio which compensates for different coupling ratios due to steric and electronic factors,

and

b)

as mixtures of resin beads which resulted from synthesis by the "portioning-mixing" method, 9 "divide, couple and recombine" process 10 or "split synthesis". 5 All these methods refer to the basic concept of "one bead - one compound ''11 as explained in Chapter 1.8.3.

2.2.2 Synthetic approaches to linear peptide libraries Based on Merrifield's original strategy of solid-phase peptide synthesis, 12 two approaches proposed by Geysen in 198413,14 using pins and by Houghton in 198515,16 based on tea-bags allowed the simultaneous synthesis of peptide libraries. These technologies made it possible to synthesise thousands of peptides in quantities of milligrams to multigrams (in tea-bags) per year.

186

2. Linear assembly strategies

The multipin synthesis constitutes a partially separated, parallel synthesis of multiple peptides on polyacrylic acid-grafted polyethylene pins in 96-well microtitre format introduced by Geysen. 13,14 This technology has been extensively used in the area of protein epitope mapping. The covalently linked peptides can be screened in a direct binding assay (ELISA). Especially designed linkers allow to cleave the peptides from the pins and to carry out the assay in solution. This technique is quite limited by the small amounts of peptides that can be generated (50 nmol up to 2 l.tmol). The multipin synthesis has also been used for the synthesis combinatorial mixtures of peptides by randomisation of distinct positions of a given peptide sequence by coupling a mixture of the 20 common L-amino acids. The "mimotope strategy" introduced by Geysen et al. led to the identification of ligands (often hexapeptides) for antibodies and other receptors. 17 Polypeptide synthesis using the tea-bag method consists of sealing 100 mg to several grams of resin into a polypropylene net. These bags thus represent spatially separated reaction compartments where peptides can be synthesised simultaneously capitalising on the fact that all of the washings, neutralisations and deprotection steps are identical and therefore not sequence dependent. The teabags are usually labelled and sorted prior to the coupling steps. Originally developed by Houghton using the Boc-/benzylester protective group strategy and diisopropylcarbodiimide (DIC) for coupling 15 this method was further developed by Jung et al. 18 using Fmoc-/tert-butylester protection and O-(benzotriazole-1-yl)tetramethyluronium tetrafluoroborate (TBTU) activation. Biological applications of the tea-bag methodology include investigations of HIV gp 41 protein by Van't H o f f et al., 19 scans of centrally truncated neuropeptide Y analogues, 2o and mapping of thymidine kinase. 21

The combination of solid-phase peptide synthesis and photolithography (light-directed combinatorial synthesis) constitutes another technology for the synthesis of spatially separated multiple parallel synthesis of peptide libraries.I, 7 Using photo-cleavable protective groups such as the N-nitroveratryloxycarbonyl group (NVOC) allows the controlled synthesis of peptide libraries by the spatially controllable addition of specific reagents to specific locations. Thereby the solid support consists of a silicon wafer functionalised with linker groups suitable for peptide synthesis. Multiple peptide synthesis has also been achieved by using polystyrene-grafted polyethylene films (PS-PE) which are produced using X-ray irradiation. 22 Small areas of the film (typically 1.5 x 3 cm) serve as reaction compartments where coupling can be carried out separately while washing and deblocking is carried out simultaneously.

187


2.3. Conformationally constrained peptides While linear peptides have been used extensively in the very early stages of lead finding (cf. Chapter 1.4) they found only limited application as therapeutic agents due to their limited protease

stability (and thus low plasma stability and bioavailability) and low penetration through cell membranes. To circumvent some of these inherent bioavailability problems associated with linear peptides several approaches have been published to modify and stabilise linear peptides by construction of peptide mimetics. 23-25 Figure 2.3.1 schematically summarises these different approaches. Figure 2.3.1

I Protein epitope mapping ]

N

] Natural peptide ligands I

small peptide sequences (tetra- to octapeptides) 1)

J

Systematic 9 reduction of the peptide sequence one amino acid at a time from the N- and C-termini (--> 4 to 8 residues) Systematic 9 replacement of L-amino acids by D-amino acids ~ Systematic replacement of side chain moieties by a methyl group ("alanine scan") Replacement 9 of coding amino acids by non-natural analogues (e.g. (~, (z-disubstituted glycines) 2) Introduction 9 of constraints by cyclisation:

- cyclic peptides depsipeptides - cyclisation via S-S bonds templates -

-

Introduction 9 of constraints by secondary structure mimetics (13-turns, loops, 13-sheets and mhelix-mimetics) Replacements 9 for the amide bond and introduction of transition state analogues

188

2. Linear assembly strategies a 1

R1 H

OH

R2

H

dipeptide mimetics 3)

" retro-inverso 5)

"

o

R2

trans-alkene isostere 4) OH

"

O

t

R

R1

o#.o

OR transition state analogue6)

r

o

dehydro amino acids 7)

References: 1) see review by Hrubi et al. 26; 2) see review by Spatola 27; 3) Refs.28-31; 4) Ref.32; 5)

Ref.33; 6) Refs.34,35; 7) Ref.36

Some of the molecular units that have been used to replace amide bonds are depicted in Figure 2.3.1 (lower part).

2.3.1. Solid-phase synthesis of unnatural amino acids and peptides Among the non-standard amino acids that have been used to chemically and conformationally stabilise small peptides, o~,~-disubstituted glycines have been studied 37 and depending on the nature of the o~-substituents they have been shown to stabilise [3-turn, 310-helical and m-helical conformations when incorporated into small peptides. Recently, a solid-phase synthesis of some of these interesting amino acids has been published by Scott et al. 38 as shown in Scheme 2.3.1. Scheme 2.3.1

Reagents and conditions: i) Ar-CHO, ii) R2-X, base; iii) HONH3§

iv) R4-COOH, PyBrOP; v) TFA

189


Deprotection of Fmoc-amino acid Wang resins under standard conditions yielded the polymerbound amino acids 1. Condensation with 3,4-dichlorobenzaldehyde gave aldimines 2. Subsequent alkylation with electrophiles such as benzyl-, naphthyl- or allylbromide in the presence of 2-[(1,1dimethylethyl)imino]- N,N-diethyl - 2,2,3,4,5,6- hexahydro- 1,3-dimethyl- 1,2,3-diazaphosphorin2(1H)-amine (BEMP) gave the disubstituted aldimines 3. Transketalisation with hydroxylamine hydrochloride yielded the free amine 4 which was acylated and cleaved to give the final product 5 in good yields and purities.

2.3.2. 13-Turn mimetics Turns are segments between secondary structural elements and are defined as sites in a polypeptide structure where the peptidic chain reverses its overall direction. They are composed of four ([3turn) or three (T-turn)amino acid residues. In contrast to a-helices or ~-sheets, turns are the only regular secondary structures which consist of non-repeating backbone torsional angles. Turns have been implicated as important sites for molecular recognition in biologically active peptides and globular proteins. 39,40 High-resolution crystal structures of several antibody-peptide complexes clearly showed turns as recognition motifs.41, 42 Furthermore, good correlations with turn conformations have been found in structm'e-activity studies of specific recognition sites in peptide hormones such as bradykinin and somatostatin.43,44 13-Turns have also been hypothesised to be involved in post-translational lysine hydroxylation, 45 processing of peptide hormones, 46,47 recognition of phosphotyrosine-containing peptides,48, 49 signal peptidase action, 50 receptor intemalisation signals,51, 52 and in glycosylation processes. 53 These findings together with the fact that turns occur mainly at the surface of proteins make them attractive targets as peptide mimetics. 25

Terminology of 13-turns

According to Venkatachalam, 13-turns are classified into conformational types depending on the values of four backbone torsional angles (O~,W1,O2,W2) (Table 2.2.1). 54

O

R 1 R2 o

0

190

R3


Table 2.2.1

02

Type ")

!

~F2

Nomenclatureb)

o

-60

:

-30

-90

i

0

0~0~

60

i

30

9o

i

o

y)'

-60

~

120

8o

i

o

BpY

60

i

-120

-80

i

0

EOt

III

-60

i

-30

-60

i

-30

~0~

III"

60

~

30

60

i

30

W

H

P

a) Turn nomenclatureaccording to Venkatalacham54 b) Turn nomenclatureaccording to Wilmot and Thornton55 A second criterion is the ocC i ~ o~Ci+ 3 distance, introduced by Kabsch and Sander, which must be shorter than 7 A (Figure 2.3.2). 56 Typical for ~l-turn motifs is a H-bond between the carbonyl group at position i and the amide NH of residue i+3. Figure 2.3.2 residue i + 1 ~ e s i d u e

i +2

residue ~

.................................... "s "'~residue i + 3

d (icct--->i+3cot ) < 7/~ To date, eight different types of [B-turns have been classified and the torsional angles (~l,~Pl,~2,~P2) of the most important naturally occurring I5-turns are depicted in Table 2.2.1.

Mimicking strategies for [I-turns Mimicking a [3-turn consists in constraining correctly four torsional angles ((I)l,(I)2,kIJl,kI/2) and four bonds (bonds a-d, cf. Fig. 2.3.3). Bonds a and d direct the entry and the exit of the peptide chain through the turn, respectively, whereas bonds b and c are responsible for the spatial dispositon of the amino acid side chains at position i+l and i+2 of a turn. The torsional angles determine the backbone geometry of the turn and consequently the shape of the turn hydrogen 191


bond. Bonds a and d, describe the vectors of the C- and N-terminal peptide chain entering and leaving the turn. The control of these vectors is essential for cases where additional amino acid residues are placed outside of the central amide unit. Figure 2.3.3

Bond b

/

0

_~1 II

Bond c I

~3

,-,

,'~. r HNV't'I ,,N% ~ = : 0 . . . . . . . H C;4 1C~f Bonda Bondd ~

Peptidic [3-turn mimetics are generally based on cyclic backbone mimetics (e.g. replacing the turn hydrogen bond by a covalent bond) or by introducing one or several unusual amino acids, which constrain the backbone in [3-turn conformations. Synthetic approaches to non-peptidic turn mimetics can be grouped into two classes: 1) external fl-turn mimetics, and 2) internal fl-turn mimetics. 25 External mimetics do not mimic per se the turn backbone but rather stabilise 13-turn geometries of an attached peptide whereas an internal [3-turn mimetic replaces the space in the turn which would normally be occupied by the peptide backbone. This methodology tries to correctly place key binding groups such as b and c (Figure 2.3.3) in 3D-space, while being less stringent with respect to the correct geometry of the turn backbone. Less effect on the backbone geometry can be expected, because only a small fragment of the peptide is replaced by the constraint. Furthermore, due to the small molecular size of the template, little steric hindrance with a receptor may be anticipated. A compilation of 13-turn stabilising templates can be found in a recent review. 25 Ellman et al. 57,58 have developed a general method for the solid-phase synthesis of ~-tum mimetics 10 composed of three readily available building blocks (Scheme 2.3.2). t~-Bromoacetic acid was

coupled to the

support-bound p-nitrophenyl

alanine 6

by

activation

with

diisopropylcarbodiimide. Subsequent treatment with the aminoalkyl thiol protected as a mixed disulfide provided the secondary amine 7. Coupling with a Fmoc-protected amino acid by activation with HATU gave 8. Deprotection and subsequent coupling of an a-bromo acid gave 9 which after reductive cleavage of the disulfide could be cyclised to give 10.

192


Scheme 2.3.2

Reagents and conditions: i) bromoacetic acid, DIC; ii) H2N-CH2-(CH2)n-SStBu; iii) Fmoc-amino acid, HATU;

iv) piperidine; v) a-halo acid, DIC; vi) PBu3, H20; vii) TMG; viii) TFA Employing this synthesis sequence turn mimetics 10 were obtained with an average purity of 75% over the 8-step process. No dimers were detected, cyclisation gave exclusively the desired macrocycles. The mimetic is constrained in a turn structure by replacing the hydrogen bond between the i and i+3-residues with a covalent backbone linkage. The flexibility of the turn mimetic and relative orientations of the side chains can be modulated by introducing different backbone linkages to provide 9- or 10-membered rings.

2.3.3. Loop mimetics In addition to the classical secondary structure elements occurring at the surface of proteins such as y- and 13-turns, 310- and a-helices and [3-sheets, loops of variable size seem to play a crucial role in many protein-protein interactions. Various amino acid derived templates have been proposed to stabilise 13-tums as external templates and a compilation of loop stabilising templates is shown in Figure 2.3.4. 59-64

193


Figure 2.3.4

A1A2--A

n

.

peptide sequence containing amino acids A1-An

Figure 2.3.5 shows a series of tricyclic xanthene-, phenoxazine- and phenothiazine-derived templates that have been shown to stabilise I~--turn conformations in attached peptides for n=2 and

4. 24 These templates were also successfully employed for the synthesis of larger loop mimetics (n < 14). Figure 2.3.5

X= O, Y= C(CH3)2 xanthenes X= O, Y= NCH3

phenoxazines

X= S, Y= NCH3

phenothiazines

HN .,.'J

Lv~O

LE-,oi,

Although larger loops are far more flexible and the conformational influence enforced by the template is reduced, the templates usually increased significantly the cyclisation yields.

194


As a validation of this concept for loop stabilisation, cyclic peptides incorporating xanthene-derived templates corresponding to the sequence of the exposed loop structure in the snake toxin

flavoridin 65,66 were synthesised on a solid support, and tested for binding to the GPIIb/IIIa receptor, and thus for inhibiting platelet aggregation. 24 The xanthene-derived loop incorporating the sequence Ile-Ala-Arg-Gly-Glu-Phe-Pro showed an ICs0-value of 15 nM and inhibited significantly platelet aggregation. In contrast, the open-chain and disulfide-bridged peptides were markedly less potent. In order to use this template approach in view of synthesising combinatorial libraries of mimetics of exposed protein loops, Waldmeier and Obrecht 67 synthesised the unsymmetrically substituted xanthene derived templates 11 and 12 (Figure 2.3.6). 25

Figure 2.3.6

These templates proved to be useful building blocks for the construction of [3-turn stabilised peptide loop libraries using the split synthesis. It was not necessary to resort to tagging strategies for compound identification, since the cyclic molecule could be linearised by amide-cleavage, which then allowed Edman-degradation of the resulting open-chain peptide, as shown schematically in Figure 2.3.7. The selective amide cleavage results from a regioselective acid catalysed y-lactone formation with concomitant liberation of the N-terminus. Since only the ringopened products are subjected to Edman-sequencing, only minute amounts of the cyclic peptide have to be cleaved for this purpose.

Figure 2.3.7

RI~o

~

P

A1-A2~-A3~An

1) O P - - > OH ,. 2) HX

R, o HN

_ -

\~)

AII ~ A 2 - - - A 3 ~ A n - N

Edman-

sequencing

H3+X

195


As an application of this concept, the template bridged cyclic peptides 13 and 16 containing the sequences Ala-Lys-Glu-Phe and Asp-Pro-Phe-Asp-Gly-Arg-Ala-Ile were synthesised by standard protocols, 68 ring-opened using methane sulfonic acid in MeOH at 50-60~

and sequenced by

Edman-degradation (Figure 2.3.8). Using the solid phase compatible template 12, which was attached via the photocleavable PPOA-linker69, 7o to a polystyrene resin, template-bridged cyclic peptide libraries were synthesised and sequenced using this strategy. Figure 2.3.8

Ph~OR5

ii,

Ph

Ala~Lys~Glu~Phe 13 R 5 = Bn 14 R 5 = H =

15

lii)

P h ~ O H HN,,,J t,,~O Alp PIiro

OH 2Me I Ala-Lys-Glu-Phe-N H3+CH3SO3 I OMe

~la Ite

Phe--Asp---Gly-Arg 16


i)

=

Ph

OH 2Me

A~p(OMe) r~

ilI~-NH3+0H3SO3

PhemAsp--Gly--Arg 17

i) MeSO2OH,MeOH,60~ ii) H2,Pd/C(95%)

The role of the xanthene-derived template can be summarised as follows: 9 As previously shown, these templates stabilise efficiently I]-tum type conformations in peptides and thus should also have a significant stabilising effect in larger loops. 9 As a consequence of conformational stabilisation, routinely increased cyclisation yields were noticed when comparing the template-bridged loops with to the non-templated or disulfidebridged peptides. 9 As an important feature, a linker group can be attached to the tricyclic skeleton of 12 which results in the possibility to attach the template onto a solid support and synthesise templatebridged cyclic peptide libraries using the split synthesis.

196


9 The photocleavable linker allows detachment of the cyclic peptide from the resin and to assess biological activity in homogeneous solution assays. 9 Peptide ring opening via intermediate y-lactone formation using methanesulfonic acid in MeOH liberated the N-terminus without concomitant cleavage of the peptide chain and allowed determination of the sequence by Edman degradation without having to resort to tagging strategies. The methodology should generally prove useful to efficiently construct loop-libraries corresponding to exposed loop regions of proteins and thus probe novel important insights into protein-protein interactions.

2.4. Peptoids As already mentioned, linear small peptides show some major drawbacks 71 for the development of bioavailable, orally active drugs. In view of using the highly efficient amide coupling chemistry in combination with easily available amino acid building blocks, the so-called "peptoids" were developed 72 first at Chiron. Figure 2.4.1 schematically compares a peptide with a peptoid backbone. Figure 2.4.1 R1

O

R2

O

R3

I PeptidebackboneI

I PeptoidbackboneI

The major difference between peptides and peptoids lies in the fact that the "side chain" substituents R1-R 3 in peptoids are attached to the amide nitrogens, thus avoiding the chiral o~centres of a peptide. There are no NH-bonds present in peptoids which has major implications on solubility, cell penetration properties and on the overall conformations which differ significantly from those of peptides. 72 In addition, compared to peptides, peptoids show an increased protease stability due to the tertiary amide bond. Three different types of building block strategies were developed for the efficient synthesis of peptoids as schematically shown in Scheme 2.4.1 (Approaches A-C). 73

197


Scheme 2.4.1

Approach A: sequential coupling of N-substituted glycines

Approach B: Sequential coupling of glycine followed by reductive amination with aldehydes

Approach C: Coupling with bromoacetic acid followed by nucleophilic displacement with amines

Reagents and conditions: i) DBU, DMF; ii) PyBOP or PyBroP, R2NFmocCH2COOH;iii) DBU, DMF;

iv) R-CHO, NaCNBHaor Na(OAc)aBH, MeOH; v) Fmoc-Gly, PyBOP or PyBroP; vi) DIC, DMF, BrCH2COOH;vii) R-NH2,DMSO.

198

2. Linearassemblystrategies Approach A is based on the classical solid-phase peptide synthesis using the required N-substituted Fmoc-protected amino acids. Thus, deprotection of resin-bound 18 under standard conditions and coupling with Fmoc-NR2CH2COOH using PyBOP or PyBroP gave 19, which was converted into the final peptoid 20.

Approach B takes advantage of a classical peptide coupling using Fmoc-glycine as key building block. Thus, 21 is converted to 22 by Fmoc-deprotection, followed by reductive amination with an aldehyde. Repetition of this sequence via 23 and 24 yields after cleavage from the resin peptoid 20. Approach C is based on tx-bromoacetic acid as key building block and starts from Rink-amine. After coupling of tx-bromoacetic acid yielding 25, followed by nucleophilic displacement with an amine, polymer-bound derivative 22 is obtained. Repetition of this cycle of events and cleavage from the resin gives rise to peptoid 20. Using the "split-mixed" methodology several targeted libraries were synthesised in order to find novel lead compounds. As one of the most striking examples, 18 pools of N-substituted glycine derived peptoids were assayed for inhibition of [3H]-DAMGO (It-specific) binding 74 to opiate receptors. The most active compound CHIR 4531 (Figure 2.4.2) was shown to inhibit [3H]DAMGO binding with K~ = 6 + 2 nM.

Figure 2.4.2

/~O N

ONH2

OH CHIR 4531

199


2.5. Oligonucleotides Similarly to the polymer-supported peptide synthesis, the synthesis of oligonucleotides developed quickly into a rapidly growing field of research. Initial pioneering work has been carded out by Letsinger and Khorana 75 as indicated in Chapter 1.2. Many polymer supports have been reported

which have been successfully used in the synthesis of oligonucleotides, including non-soluble polymers such as polyacrylamide based resins, porous glass and soluble polymers such as polyethyleneglycol derived resins (Chapter 3.8). The most important strategy for the linear synthesis of oligonucleotides has been developed by M. Caruthers. 76 Nowadays, the phosphite triester method is widely used in the automated synthesis of oligonucleotides on silica. The principle is shown in Scheme 2.5.1. Scheme 2.5.1

oligonucleotide

OMT .. basel o

MeO " P ' N ' ~ 30 Reagents and conditions: i) dichloroacetic acid, CH2CI2;ii) 30, MeCN iii) a) acetic anhydride, b) 12.

(DMT: dimethoxytrityl)

200


The key building blocks include the appropriately protected deoxynucleoside 3'-phosphoramidites 30. They are used in every cycle to prolong the oligonucleotide chain, followed by oxidation with iodine to obtain the desired phosphate triester 29.

2.6. Oligosaccharides Oligosaccharides fulfill in nature several important functions. They serve as structural materials

(e.g. cellulose), energy storage (e.g. glucose and starch) and are important recognition elements on the cell surface. 77 They are usually composed of less than 20 monosaccharide units and occur as conjugates of lipids and proteins. 78 While in the synthesis of naturally occurring oligosaccharides the use of enzymes (glycosyl transferases) proved very useful due to their substrate specificity and stereospecificity and the possibility to work without protective groups, 79 the synthesis of unnatural oligosacchafides still relies on synthetic methods. 8~ Among the basic biopolymers, the development of a polymer-supported synthesis of oligosaccharides has turned out to be the most difficult one. This is due to the requirement of stereocontrol in the formation of the glycosidic bond and the wide range of orthogonal protective groups for primary and secondary alcohols. At present, polymer-supported synthesis of oligosaccharides cannot yet compete with the classical syntheses in solution. 81 Incomplete glycosylation reactions with insufficient degree of stereocontrol, instability of the glycosyl donors under the prolonged reaction conditions required in solid-phase reactions and problems associated with incomplete protection and deprotection procedures constitute certainly some of the reasons for slower progress in this field. Soluble polymers might be the solution for the future. 82 Two major coupling strategies were elaborated for the formation of glycosidic bonds on solid support. Scheme 2.6.1 shows the glycal method developed by Danishefsky et al. 83,84 A polystyrene-bound glycal 31 is activated for glycosyl donation by formation of the 1,2-epoxide 32. Addition of a glycosyl donor (33) generates the glycosidic bond under concomitant ringopening and formation of a secondary alcohol in 34 which can directly be glycosylated (36). The other possibility is to activate the glycal as previously described and couple to 33 to give trisaccharide 37. It is interesting to note that a silicon-based linker strategy was successfully employed.

201


Scheme 2.6.1

Reagents and conditions: i) 3,3-dimethyldioxirane, CH2CI2, ii) ZnCI2, THF; iii) Sn(OTf)2, DTBP, THF.

The second strategy reported by Kahne et al. 85-87 is depicted in Scheme 2.6.2. In this sulfoxidebased method it is possible to selectively form a- or [3-glycosidic bonds. Repeated glycosylation drove the reaction to completion. Oxidative cleavage with mercuric tfifluoroacetate gave disaccharide 42 and 45 in 67% and 64% yield over two steps. The yields were higher on solid support as compared to those obtained in solution for this type of glycosidic linkages.

202


Scheme 2.6.2

Reagents and conditions: i) Cs2CO3, Merrifield resin; ii) Tf20, 2,6-di-tert-butyl-4-methylpyridine,

CH2CI2,-60 to-30~

iii) Hg(OCOCF3)2, CH2CI2, H20, r.t.

Kahne, Still and coworkers reported recently the solid-phase parallel synthesis and screening of a

carbohydrate library using the sulfoxide glycosylation reaction. 88 The library was constructed on TentaGel | resin and contained approximately 1300 di- and trisaccharides. A chemical tag was incorporated after every reaction step in order to monitor the history of the beads and to facilitate structure elucidation. The synthesis of the library is outlined in Scheme 2.6.3.

203


Scheme 2.6.3

As starting building blocks were used 6 glycosyl acceptors which were attached to a TentaGel NH resin prior to coupling with 12 different gycosyl donors using the split-mixed synthesis. The amino group was derivatised with twenty different acylating agents. After deprotection, the library was assayed on bead against Bauhinia purpurea lectin. Two compounds could be identified which bind more tightly to the receptor than the nattwal ligands. Carrying out the assay on bead mimicks oligosaccharides bound to cell membranes. Another solid-phase synthesis of oligosaccharides on soluble PEG will be discussed in Chapter 3.8.

204


2.7. Oligocarbamates and oligoureas Besides the amide bond present in peptides, the carbamate and urea groups constitute additional chemically stable linkages for oligomeric compounds. 89 The first syntheses of oligocarbamates on solid supports were based on the sequential condensation of aminoalcohols9~ derived from oramino acids shown in Scheme 2.7.1. Scheme 2.7.1

Reagents and conditions: i) hv (350nm); ii) p-NO2-CsH4OCOCH2CHR2NH-NVOC; iii) R3-COX; iv) TFA

Coupling of 46 with the corresponding p-nitrocarbonates of N-veratroyl (NVOC) protected aminoalcohols 47 gave polymer-bound carbamates 48 in high yields. Photochemical deprotection of the NVOC-group (350 nm), followed by a second coupling of a building block of type 4 7 yielded polymer-bound 49. Deprotection of the amine and subsequent acylation followed by cleavage from the solid support gave polycarbamates of type 50. The urea moiety is an important structural element present in a series of enzyme inhibitors 91 such as HIV-1 protease inhibitors of type 51 as depicted in Figure 2.7.1.

205


Figure 2.7.1

HO,

O

R'N..~.N-R NO

N

Ph_~N I . ' ~ N ~ Ph

OH

NO

51

ON 52

Recently, the oxamate analogue 52 (KI = 42 nM) has been prepared and was shown to be 10-fold more active than the corresponding cyclic urea for inhibition of HIV pR.92 For the synthesis of oligoureas any suitably mono-protected diamine of type 53 can serve as a starting point as depicted in Scheme 2.7.2. Attachment of the free amine to the solid support (e.g. 54), followed by deprotection and conversion into an isocyanate by treatment with triphosgene generated polymer-bound isocyanate 56 ready for treatment with a second mono-protected diamine to yield 57 after deprotection. Capping of the terminal amino group with e.g. an isocyanate (R"N=C=O) and cleavage from the resin generated products of type 58. Reaction sequences of this type have been reported by Burgess et al. 93 Scheme 2.7.2

Reagents and conditions: i) CH2CI2;ii) NH2NH2.H20,DMF 15h; iii) (CI3CO)2CO,NEt3,CH2CI2;

iv) H2N-R1-NPt;v) R2-N=C=O;vi) base

206


2.8. Peptide-Nucleic acids (PNA) Similarly to peptides, oligonucleotides are readily biologically degraded by various enzymes. Their use as orally active therapeutic agents is therefore very problematic. With the aim to overcome these problems, hybride oligomers designated as peptide-nucleic acids (PNA) have been reported for the first time in 1991 by Nielsen et al. 94 The synthesis is schematically depicted in Scheme 2.8.1.

Scheme 2.8.1

Reagents and conditions: i) DCC, pentafluorophenol; ii) BocNH(CH2)2NHCH2COOH; iii) PS-NH2

Starting from the modified bases of type 59, activation to the corresponding pentafluorophenyl ester (PfpO), coupling to N-(N-Boc-aminoethyl)glycine and a second activation leads to the monomeric PNA-building block 60 (corresponding to thymine) which can be coupled to a polymeric support to yield 61. Repetitive couplings of PNA-monomers and f'mal cleavage from the resin gave rise to PNA-products of type 62 which are currently under evaluation as antisense probes for DNA therapy and diagnostic purposes.

207


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Synthesis, Structure and Function. Proceedings of the Seventh American Peptide Symposium, D. H. Rich and V. J. Gross (Ed.), p. 685, Pierce Chemical Company: Rockford, IL (1981). (44) D. J. Kyle, S. Chakravarty, J. A. Sinsko and T. M. Storman, J. Med. Chem. 1994, 37, 1347. (45) P. Jiang and V. S. Ananthanarayanan, J. Biol. Chem. 1991, 266, 22960. (46) N. Brakch, M. Rholam, H. Boussetta and P. Cohen, Biochemistry 1993, 32, 4925.

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(47) L. Paolillo, M. Simonetti, N. Brakch, G. D'Auria, M. Saviano, M. Dettin, M. Rholam, A. Scatturin, C. DiBello and P. Cohen, EMBO J. 1992, 11, 2399. (48) V. Mandiyan, R. O'Brien, M. Zhou, B. Margolis, M. A. Lemmon, J. M. Sturtevant and J. Schlessinger, J. Biol. Chem. 1996, 271, 4770. (49) T. Triib, W. E. Choi, G. Wolf, E. Ottinger, Y. Chen, M. Weiss and S. E. Shoelson, J. Biol. Chem. 1995, 270, 18205. (50) G. A. Barkocy-Gallagher, J. G. Cannon and P. J. Bassford, J. Biol. Chem. 1994, 269, 13609. (51) A. Bansal and L. Gierasch, Cell 1991, 67, 1195. (52) W. Eberle, C. Sander, W. Klaus, B. Schmidt, K. von Figura and C. Peters, Cell 1991, 67, 1203. (53) B. Imperiali, J. R. Spencer and M. D. Struthers, J. Am. Chem. Soc. 1994, 116, 8424. (54) C. M. Venkatachalam, Biopolymers 1968, 6, 1425. (55) C. M. Wilmot and J. M. Thornton, J. Mol. Biol. 1988, 203, 221. (56) W. Kabsch and C. Sander, Biopolymers 1983, 22, 2577. (57) A. A. Virgilio and J. A. Ellman, J. Am. Chem. Soc. 1994, 116, 11580. (58) J. A. Ellman, Acc. Chem. Res. 1996, 29, 132. (59) R. Sarabu, K. Lovey, V. Madison, D. C. Fry, D. N. Greeley, C. M. Cook and G. L. Olson, Tetrahedron 1993, 49, 3629. (60) D. L. Boger, M. A. Patane and J. Zhou, J. Am. Chem. Soc. 1995, 117, 7357. (61) R. Beeli, M. Steger, A. Linden and J. A. Robinson, Helv. Chim. Acta. 1996, 79, 2235. (62) C. Bisang, C. Weber and J. A. Robinson, Helv. Chim. Acta 1996, 79, 1825. (63) F. Emery, C. Bisang, M. Favre, L. Jiang and J. A. Robinson, J. Chem. Soc., Chem. Commun. 1996, 2155. (64) M. Pfeifer, A. Linden and J. A. Robinson, Helv. Chim. Acta. 1997, 80, 1513. (65) W. Klaus, C. Broger, P. Gerber and H. Senn, J. Mol. Biol. 1993, 232,897. (66) H. Senn and W. Klaus, J. Mol. Biol. 1993, 232,907. (67) P. Waldmeier, Ph.D thesis, University of Ziirich (1997). (68) W. Bannwarth, F. Gerber, A. Grieder, A. Knierzinger, K. Miiller, D. Obrecht and A. Trzceciak, Can. Pat. Appl. CA 2101599, 1995. (69) N. A. Abraham, Tetrahedron Lett. 1991, 32,577. (70) D. Bellof and M. Mutter, Chimia 1985, 39, 10. (71) J. J. Plattner and D. W. Norbeck, Obstacles to drug development from peptide leads, in: Drug Discovery Technologies, C. R. Clark and W. H. Moos (Ed.), p. 92, Ellis Horwood Ltd.: Chichester, U.K. (1990). (72) L. S. Richter, D. C. Spellmeyer, E. J. Martin, G. M. Figliozzi and R. N. Zuckermann, Automated synthesis of non-natural oligomer libraries: the peptoid concept, in: Combinatorial Peptide and Nonpeptide Libraries, G. Jung (Ed.), p. 387, VCH: Weinheim (1996).

210

Chapter2; References (73) R. J. Simon, R. S. Karua, R. N. Zuckermann, V. D. Huebner, D. A. Jewell, S. Banville, S. Ng, L. Wang, S. Rosenberg, C. K. Marlowe, D. C. Spellmeyer, R. Tan, A. D. Frenkel, D. V. Santi, F. E. Cohen and P. A. Bartlett, Proc. Natl. Acad. Sci. USA 1992, 89, 9367. (74) M. G. C. Gillan and H. C. Kosterlitz, Br. J. Pharm. 1982, 77, 461. (75) R. L. Letsinger and V. Mahadevan, J. Am. Chem. Soc. 1965, 87, 3526. (76) M. H. Caruthers, Science 1985, 230, 281. (77) C. M. Taylor, Strategies for combinatorial libraries of oligosaccharides, in: Combinatorial Chemistry, S. R. Wilson and A. W. Czamik (Ed.), p. 207, John Wiley & Sons, Inc.: New York (1997). (78) H. Paulsen, Angew. Chem. Int. Ed. Engl. 1990, 29, 823. (79) E. J. Toone, E. S. Simon, M. D. Bednarsky and G. M. Whitesides, Tetrahedron 1989, 45, 5365. (80) K. Toshima and K. Tatsuta, Chem. Rev. 1993, 93, 1503. (81) Y. Wang, H. Zhang and W. Voelter, Chem. Lett. 1995, 273. (82) D. J. Gravert and K. D. Janda, Chem. Rev. 1997, 97, 489. (83) J. T. Randolph, K. F. McClm'e and S. J. Danishefsky, J. Am. Chem. Soc. 1995, 117, 5712. (84) S. J. Danishefsky, K. F. McClure, J. T. Randolph and R. B. Ruggeri, Science 1993, 260, 1307. (85) L. Yan, C. M. Taylor, R. Goodnow Jr. and D. Kahne, J. Am. Chem. Soc. 1994, 116, 6953. (86) S.-H. Kim, D. Augeri, D. Yang and D. Kahne, J. Am. Chem. Soc. 1994, 116, 1766. (87) D. Kahne, S. Walker, Y. Cheng and D. Van Engen, J. Am. Chem. Soc. 1989, 111,6881. (88) R. Liang, L. Yan, J. Loebach, M. Ge, Y. Uozumi, K. Sekanina, N. Horan, J. Gildersleeve, C. Thompson, A. Smith, K. Biswas, W. C. Still and D. Kahne, Science 1996, 274, 1520. (89) J. S. Frtichtel and G. Jung, Angew. Chem. Int. Ed. Engl. 1996, 35, 17. (90) C. Y. Cho, E. J. Moran, S. R. Cherry, J. C. Stephans, S. P. A. Fodor, C. L. Adams, A. Sundaram, J. W. Jacob and P. G. Schultz, Science 1993, 261, 1303. (91) P. Y. S. Lam, P. K. Jadhav, C. J. Eyermann, C. N. Hodge, Y. Ru, L. T. Bacheler, J. L. Meck, M. J. Otto, M. M. Rayner, Y. N. Wong, C.-H. Chang, P. C. Weber, D. A. Jackson, T. R. Sharpe and S. Erickson-Viitanen, Science 1994, 263, 380. (92) P. K. Jadhav, W. F.J. and M. Hon-Wah, Bioorg. Med. Chem. Lett. 1997, 7, 2145. (93) K. Burgess, D. S. Linthicum and H. Shin, Angew. Chem. Int. Ed. Engl. 1995, 34, 907. (94) P. E. Nielsen, M. Egholm, R. H. Berg and O. Buchhardt, Science 1991, 254, 1497.

211


Chapter 3

Library Synthesis in Solution Using Liquid-Liquid and Liquid-Solid Extractions and Polymer-Bound Reagents 3.1. General As mentioned earlier in Chapter 1.8, solution-phase chemistry has the advantage over solidsupported chemistry in that less effort has to be put into method development work and that essentially the whole plethora of organic reactions is available. Strategies that can be employed in order to reduce the tedious purification procedures associated with solution-phase chemistry will be discussed in the following paragraphs. Lets consider the simple case of an amide library (R1CONHR z) generated from acid R~COOH using an intermediate activation followed by treatment with amines R2NH2 as shown in Figure 3.1.1.

Figure 3.1.1 --N

RI--COOH 1 (1 eq)

/--k

O

R2- NH2 (1.1 eq)

k__/ (1.1 eq)

O

O RI.,,~ N ,R2 H

2

(1.1 eq) By-products: N-methylmorpholine hydrochloride, 2-methylpropanol, excess amine, excess base and excess chloroformate

Although this reaction is known to proceed in high yields it produces the by-products mentioned in the above Figure. In the following paragraphs a number of approaches to reduce the work-up efforts will be discussed: 9 Multicomponent one-pot reactions 9 Multigeneration reactions 9 Liquid-liquid phase extractions (LPE) 9 Liquid-solid phase extractions (SPE) using polymer-bound scavengers 9 Solution reactions using polymer-bound reagents or catalysts

213

3. Library synthesis in solution using fiquid-fiquid and fiquid-solid extractions and polymer-bound reagents

Multicomponent one-pot reactions producing no by-products The first strategy m circumvent laborious extraction and purification procedures is to perform the amide formation reaction in a multicomponent format, which allows the synthesis of the amide library without vessel transfer already in the screening format (usually 96-well plates). Thus, using the Ugi four component reaction (entry a) or 3-amino-2H-azirines I (entry b) the peptide coupling can be carried out without activation of the acid derivative (Figure 3.1.2). Virtually all the atoms of all the reagents are present in the product. Figure 3.1.2

entry a:

O

1

4

5

6

a4

entry b:

R2

R1-COOH + R2-CHO + R3-NH2 + Ra-NC

R1.COOH

'

+

o

N 1

R4 R'-COO

O

8

R2

+ Rs"N'~'~R 3 N+

_

R4 ~' '

R 5"

R'P~

R2

R3

:

R4 Ni~

a2

r~

NH

R 5"" , ~ R

3

~ - O R'

While the azirine reaction proceeds in essentially quantitative yield producing no by-products, the Ugi reaction usually yields products of type 7 in 60-90% yield along with some starting materials

1, 4, 5 and 6 which can be trapped using a polymer-supported quenching (PSQ) method of purification as shown later.

Multigeneration reactions The concept of high yielding multigeneration reactions in which an essentially quantitative transformation generates a novel functional group ready for being engaged in the next step has been developed by Boger et al. 2 This strategy offers the benefit that the amount of by-products in the reaction mixture can be minimised and separated by simple extractions. As a consequence, the last generation products are not contaminated with products from previous generations (Figure 3.1.3).

214

3.1. General

Figure 3.1.3

/..~,O Boc-N

O

R1R2NH

/~,O "

O

Boc-N

N - R1

) R2 HOOC

,,.

O~..N/__ CONR1R2 R4

k---CONHR3

Liquid-liquid phase extractions Excesses of reagents and by-products are removed by simple acid-base aqueous extractive workup procedures which ultimately can be automated. Looking at our model case shown in Figure

3.1.1 it is obvious that aqueous extraction is efficient for the removal of several by-products and excesses of reagents.

Basic extraction: removal of remaining acid and saponification of excess chloroformate. Acidic extraction: elimination of basic components (N-methylmorpholine and excess amine). In the organic phase remains: product 3 and 2-methylpropanol (which can be evaporated).

Liquid-solid phase extractions using polymer-bound scavengers This strategy, although quite expensive, offers the advantage that excesses of reagents and byproducts can be removed by simple filtration. Refering to our model reaction, the following strategies can be considered (Figure 3.1.4).

Figure 3.1.4

The organic base is covalently linked to an insoluble support, removing in the first step of the process the hydrochloride salt generated in the course of the reaction without aqueous work-up.

215

3. Library synthesis in solution using liquid-liquid and liquid-solid extractionsand polymer-bound reagents

After amide coupling, the excess of amine can be easily sequestered using an acidic ion exchange resin. This protocol allows removal of by-products and excess reagents by simple filtrations generating products of high purity.

Solution reactions using polymer-bound reagents or catalysts For this purpose, our model reaction can be modified as shown in Figure 3.1.5 using a polymerbound chloroformate linking the mixed anhydride intermediate to a solid support and, thus, allowing easy removal of excess base by simple washing. After coupling with amines R2-NH2, only amide 3 and excess amine remain in solution which can be easily separated as previously described. Figure 3.1.5

216


3.2. Applications of solution-phase tion reactions

multicomponent and m u l t i g e n e r a -

3.2.1. Optimisation of the biological activity using a genetic algorithm Genetic algorithms constitute an interesting approach for rational optimisation of multiparameter systems. Applied to combinatorial chemistry this means that starting from a given set of variables a specific parameter is optimised, in this case biological activity, using the genetic operations replication, mutation and crossover. As exemplified in Scheme 3.2.1, Weber et al. 3 used a genetic algorithm to optimise the biological activity of thrombin inhibitors. Scheme 3.2.1 O RI~ /

+ R2~ O

OH 1

H 2

R4~

"

R1 + R4--N

/ R3 O

+ R3---NH2 3

+ R4~NC

5

6

4

Based on the building blocks used for the most active products of the first generation and applying the rules of the genetic algorithm (mutation and crossover) a new set of inputs was determined and used for the synthesis of the next generation. After 16 generations, the biological activity of the most active compounds laid in the submicromolar range. The process was continued for twenty generations corresponding to 400 synthesised products (0.25% of the possible 160'000). The two most active compounds out of this library are shown in Figure 3.2.1. Figure 3.2.1

o,,,o, . ~ ~ S ~

o 0

I"t2

o,, ,o

~OH CI-

H2

Sv

H

H2Cl H2

217


3.2.2. Synthesis of heterocycles using amino-azirine building blocks A nice example of a high-yielding two component reaction incorporating all atoms in the products constitutes the ring-expansion reaction of 3-amino-2H-azirines 7 with NH-acidic heterocycles4-7 as shown in the following examples (Scheme 3.2.2).

Scheme 3.2.2

R1

R2N , ~ N " R `

+

R5

NH ~)~

R

7

=

...

O

H

D 6 ~ _ ~ N - - ~ R2 ~ ~)2 W:NR3R4

8

1

R1 H N ' ~ R2

a 1

H 2 O_- .,.N'~ R R3

a

a3

R1 R2N ~ N'R4

~2

O,,, ,O

02 O

~'

10

,#n

~ ~

a4

"1~1"R3

N/ "R2 J

11

Reaction with 4-membered cyclic sulfonamides 8 afforded 7-membered heterocycles 9 in high yield (60-90%), and reaction with 6-membered sulfonamide 10 (n=l) proceeded in 85-99% yield incorporating all atoms of both building blocks into the products. No by-products were thus formed.

3.2.3. The use of l-isocyanocyclohexene in Ugi four component condensations The lack of commercially available isocyanides is one of the major restrictions of the Ugi four component reaction. A solution to this problem has been presented by Armstrong et al. 8 The use of 1-isocyanocyclohexene permitted facile conversion of the Ugi products into several new core structures as shown in Scheme 3.2.3.

218

3.2. Applicationsof solution-phase multicomponentand multigeneration reactions

Scheme 3.2.3 o

O 14

R1

,NH2

15 R1-COOH

4

R2-NH2

3

R3-CHO

2

~

o L oR' R1JL. O

R3

O

NC

12

R2 0 16 R3 SR 4

13

~

17 N .R2

R3 H

18

R4

R5

RI~R R2

3

19

Acidic hydrolysis of the reactive enamide led to the corresponding carboxylic acids 14 whereas alcoholysis gave esters 16 and aminolysis amides 15. The mechanism of the hydrolysis was shown to proceed via miinchnone derivatives 20 which, instead of being opened with a nucleophile, reacted as a 1,3-dipole in [3+2] cycloaddition reactions with propiolic esters or acetylene dicarboxylic esters to give after elimination of carbon dioxide protected pyrroles 19 (Scheme 3.2.4)

219

3. Library synthesis in solution using liquid-fiquid and fiquid-solid extractions and polymer-bound reagents

Scheme 3.2.4

~N~~ ~ ,+~ N R1 ~

R 2 R1 .'N~ =

:Nu ,. R1

~O

Ra

Nu

O-

2O I R4 ~ R4

R4

R4

RI~R

3

I

R2

19 Cyclisation was achieved by intramolecular substitution as exemplified by the synthesis of 1,4benzodiazepine-2,5-diones 18.

3.2.4. Multigeneration synthesis of a thiazole library Maehr et al. 9 reported an elegant multigeneration approach towards the synthesis of a thiazole

library in solution using the Hantzsch thiazole synthesis (Scheme 3.2.5). Starting from (2aminothioxoethyl)phosphonic acid diisopropyl ester 21 and 10 different o~-halo ketones 22, a first set of thiazoles of type 23 was generated. Subsequent Wittig-Horner reaction with 7 nitrobenzaldehydes led to the second generation of thiazoles 24, which after reduction of the nitro group gave the third generation of products 25. Acylation with 10 different cyclic anhydrides furnished the fourth generation of thiazoles 26.

220


Scheme 3.2.5

O iPrO == iPrO'

S

-P.,). NH2 21

O

ii)

S

= iPrO"I~.v~N~R1,

"

iPrO

O2N

23

R1..L..x

24

O

22

S

~-zi yY

O

O HN HOOc"Z'Y " ~ O

26

iv)

H2N~

25

Reagents and conditions: i) MeOH, A; ii) nitrobenzaldehyde, K2CO3;

iii) SnCI2, EtOH, 55~

iv) 9 toluene, 90~

221


3.3. Applications of liquid-liquid phase extractions 3.3.1. Multigeneration synthesis using an "universal template" Boger et al. 2,1~

described a simple, versatile and general approach to a solution phase, parallel

synthesis of conformationally flexible products of type 30 (Scheme 3.3.1) on a multi-milligram scale. Scheme 3.3.1

Boc-N

O

i)

0

26

Boc-N

,/._~/O

NHR1

'~

ii)

~

Boc-N

/ --cONHR1 ~"" CONHR2

HOOC

27

28 iii)

O•__

/--CONHR1 iv) N ~ R3 ~....-CONHR 2

30

/---CONHR1 HN ~---CONHR 2

29

Reagents and conditions: i) H2NR1;ii) PyBOP, DIEA, H2NR2; iii) HCI, dioxane;

iv) WCOOH, PyBOP, DIEA Thus, a 1158 compound library with a high degree of diversity was synthesised using the following procedure: Nucleophilic ring-opening of symmetrical anhydride 26 with different amines gave acids 27, which were purified by acid/base extraction and further coupled to a second amine to give 28. Liquid/liquid extraction allowed the removal of coupling reagents and excess amine. After deprotection of the secondary amine and acylation under the same standard conditions and purification by acid/base extraction, the products 30 were isolated in overall yields ranging from 10-71% and in purities >90%.

3.3.2. Non-aqueous liquid-liquid extraction using fluorinated solvents Fluorocarbon-derived solvents are usually immiscible in organic solutions and can therefore be used in standard liquid/liquid extractions. Curran and Wipf developed a new strategy in which a fluorinated substrate was linked to one of the starting materials thus rendering it soluble in fluorinated solvents. 12,z3 The principle is depicted in Figure 3.3.1.

222

3.3. Applications of liquid-liquid phase extractions

Figure 3.3.1 liquid phase chemistry

| (~

+

I

I

substrate I

(~

product + excess reagents

fluorous substrate

liquid/liquid extraction

@

+

]

[product

"

cleavage

(~

J

product

[

After every reaction step, the product can be extracted from the 'organic' phase with fluorinated solvents. Excess reagents remain in the 'organic' phase and can be easily removed. The strategy has also been successfully used in a

Ugi multicomponent-type reaction condensing derivatised Scheme 3.3.2. The reaction

benzoic acid 31 with amines, aldehydes and isonitriles as shown in

was carried out in TFE and products 32 were isolated by liquid-liquid extraction. After cleavage of the fluorinated chain with TBAF followed by another extraction, the desired products 33 were isolated in good to excellent yields and with purities >80% (determined by GC).

Scheme 3.3.2

ff~

COOH

~.s, i...,98%. Scheme 3.4.1

RlmNH2

i) R2-COCI ii) H20

Amberlite| O IRA-68 R2JJ~N.R1 + R2-COOH ~ H R2-COO Res+ D.

O R2J~N

o

a1

yield >84% purity >98%

Similarly, excess amines could be extracted with acidic ion exchange resins as exemplified by the same group in the synthesis of ureas starting from isocyanates and amines. 15 A different approach has been chosen by Siegel et al. at Eli Lilly. After a reductive amination reaction (depicted in Scheme 3.4.2) using one equivalent of amine and three equivalents of aldehyde the reaction mixture was loaded on an ion exchange column. The desired resin-bound amines could be separated from excess aldehyde by filtration and the products were subsequently washed from the ion exchange resin by treatment with methanolic ammonia. Scheme 3.4.2

R i m NH2

224

R2-CHO (3eq) --MeOH NaBH4

R2 / R1- NH

ion exchange R2 NH3/MeOH resin (SCX) / _--~ R1-NH2+ res

R2 RI_NH


An alternative cleavage procedure from ArgoGel-Wang resin has been explored by Porco Jr. et al. 16 as the standard cleavage conditions (TFA) provided products only in insufficient purity.

Oxidative cleavage using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) proceeded very cleanly but isolation of the products remained tedious. A mixed bed ion exchange scavenger was developed which reduced excess DDQ to DDQH and subsequently scavenged DDQH from the reaction solution. Amberlyst| A-26 (OH-form) was loaded with ascorbic acid for the reduction and Ambedyst| A-26 (HCO3) was used for the subsequent trapping of DDQH.

3.4.2. Solid-phase extraction using covalent scavengers Reagents of by-products can also be trapped by covalent binding to a polymer. Kaldor et a/. 17,18 reported the use of aminomethyl polystyrene for the extraction of isocyanates, acid chlorides or sulfonyl chlorides from reaction mixtures (Scheme 3.4.3, entry a). Similarly, amines were trapped with polymer-supported isocyanates, acid chlorides or aldehydes (Scheme 3.4.3, entry b). Scheme 3.4.3

225


3.4.3. Synthesis of a thiazole library using liquid- and solid-phase extractions As an example, we present a solution-phase multigeneration strategy towards highly substituted thiazoles based on the Hantzsch condensation of thioureas 33 with 2-bromomethyl ketones 34 to give 2-aminothiazoles 35 in high yields, as shown in Scheme 3.4.4, using liquid-liquid phase extraction (LPE) and liquid-solid phase extraction (SPE). Scheme 3.4.4

RO2C'~IIN=C=O 42=RO2C.,~NHH~NH2

ii)

R3

RO2C

R1 I

H N

R3

40

O

43

~R3 0~~~

[2ndgenerati~ R2

41

R=Me

inorganic salts removed by LPE iii)['-'~" - 44 R=H organic by-products removed by SPE R4

iv)

N

3 rd generationl

R4R5NH, 46

N

4 th generation R2

45

Reagents and conditions: i) a) EtOH, dioxane, 60~

b) 36 or 38; ii) a) toluene, 70~

iii) LiOH, dioxane, H20, r.t.; iv) EDCI, cat. DMAP, CH2CI2, r.t. (36=N-(4-carboxyphenyl)thiourea; 42= 1,2-diaminoethane)

226

b) 42;


The excess of 34 was trapped either with N-(4-carboxyphenyl)thiourea (36) yielding 37 and removed by LPE, 19 or with polymer-bound thiouronium salt 38 to yield polymer-bound imidazole 39 (in analogy to a liquid-phase strategy developed by Dodson et al. 2~ and removed by SPE. Subsequent treatment of thiazoles 35 with a series of amino acid-derived isocyanates 40 gave the second generation of thiazoles 41 in essentially quantitative yields. Excess of 40 was trapped with 1,2-diaminoethane (42) to yield the highly polar ureas 43 which were easily removed by SPE. Saponification gave the third generation of thiazole acids 44, which could be efficiently transformed into the corresponding amides 45 by EDCI (1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride) activation and coupling with amine 46. Again, all the excesses of reagents could be removed easily either by SPE or LPE. This aminothiazole synthesis, comprising four generations of products 35, 41, 44 and 45, could be optimised, automated and performed on a robotic system.

3.4.4. Synthesis of a pyrazole library using purification by solid phase extraction Another example of a multistep synthesis using only PSQ purification procedures was described by Hodges et al. 21 In the first step, 1,3-diketone 47 was reacted with an excess of hydrazine 4 8 in the presence of morpholinomethyl-polystyrene (49). Removal of excess 48 by quenching with polymer-bound isocyanate 50 afforded pyrazole 51 with a purity of 97% (HPLC) but in quite moderate yield (48%). In the second step, 51 was converted into a mixed anhydride (by treatment with isobutyl chloroformate in the presence of 49) and subsequently transformed in situ into 5 3 by reaction with an amine. Addition of the polymer-bound reagents 50 and 52 removed excesses of chloroformate and amine by filtration and 53 was isolated in 75% yield with a purity of 97% (HPLC).

227

3. Library synthesis in solution using liquid-liquid and liquid-solid extractions and polymer-bound reagents

Scheme 3.4.5

3.5. Applications of polymer-bound reagents 3.5.1. Polymer-supported Burgess reagent The Burgess reagent 22 (54, Figure 3.5.1) is a versatile and mild reagent for the cyclodehydration of ]3-hydroxyamides or thioamides to produce oxazolines or thiazolines.

Figure 3.5.1 0

0

" Et3~,S..N.JJ..O/

0

+ S"

A,~O~~) NI]~.O 0

k

54

55

o

Y

J

PEG-OMe

The problem related with this commercially available compound is its sensitivity towards oxidation as well as moisture. Wipf et al. 23 reported the synthesis of a PEG-grafted Burgess reagent (55) which proved to be highly effective for cyclodehydration reactions as shown in Scheme 3.5.1.

228

3.5. Applications of polymer-bound reagents

Scheme 3.5.1 R2

X

i)

R1

.{

HO

=

R3

R3

(X = O, S) Reagents and conditions: i) 55, dioxane/THF (1:1 ), 85~

3h

Cyclodehydrations with PEG-bound Burgess reagents proceeded in high yields (76-98%), with little (99%. In a similar approach, a (DHQD)2PHAL ligand was bound to a MeO-PEG-NH 2 resin to give the soluble catalyst 78. 47 Dihydroxylation of a variety of substrates using 78, OsO4 and K3Fe(CN)6 proceeded in good to excellent yields (83-95%) and high enantiomeric excesses (>97%). The polymer-bound catalyst is completely soluble in tert-butanol/water or acetone/water and accelerates the reaction similar to the free ligand. In addition, precipitation with diethyl ether allows virtually quantitative recovery of the catalyst.

236


Sharpless epoxidation of allylic alcohols The asymmetric epoxidation of allylic alcohols developed by Sharpless 48 is a key reaction in asymmetric organic synthesis (Scheme 3.6.2). Enantiomeric purities of the obtained products are usually very high (>98% e.e.).

Scheme 3.6.2 -"

R

OH

Reagents and conditions: i) L-(+)-diethyl tartrate, Ti(O-iPr)4, tBuOOH, molecular sieves 4A, CH2CI2, -20~

Thus, polymeric tartrate esters 79 (Scheme 3.6.3) were synthesised and tested as catalysts in asymmetric Sharpless-epoxidations.

Scheme 3.6.3 COOH HO

COOH

L-(+)-tartaric acid

O +

HOm(CH2)n--OH

,

HO'""~'O- (CH2)_)_x O

n = 2, 6, 8, 12

79

Reagents and conditions: i) p-toluene sulfonic acid, ca. 120~

3d

Unfortunately, epoxidations of trans-hex-2-en-l-ol using the polymeric catalysts 79 gave unsatisfactory results. Yields of isolated products varied between 44 and 80%, whereas enantiomeric excesses ranged from 8-79% e.e. depending on the amount of catalyst and titanium tetraisopropoxide used. A homogeneous experiment using L-(+)-diethyl tartrate gave the desired product with 91% e.e. It has to be noted that the polymer-supported version of the Sharpless epoxidation was clearly less effective than the corresponding reaction in solution. 49

Hydroxylation of benzene using a polymer-supported VO ~+ catalyst The direct formation of phenols from benzene has been studied with several transition metal complexes. However, the complexes are usually used in stoichiometric amounts and cannot be recycled.

237

3. Library synthesis in solution using fiquid-fiquid and fiquid-solid extractionsand polymer-bound reagents

Based on this observation, Kumar et al. 5~ have developed a polystyrene-based vanadyl complex 80 (Scheme 3.6.4), generated from diethanolamine, L-tyrosine, salicyl aldehyde and VO(acac)2, to perform hydroxylations of benzene using 1 mol% of 80 and 1 equivalent of H202. After stirring at 65~ for 6h, a conversion of 30% was detected. The phenol could be easily separated from unreacted benzene by distillation. Scheme 3.6.4

O

H202(1eq),80(lmo1%),MeCN,65~

[~OH

Although the reaction proceeded with only 30% conversion it offers some potential for further investigations. The catalyst could be recovered by simple filtration and re-used another ten times before deterioration was observed.

3.6.2. Catalysts for reductions The use of oxazaborolidine catalysts in asymmetric reductions of ketones has been extensively studied by Corey et al. 51 Recently, a polymer-bound oxazaborolidine45 (Scheme 3.6.5) was developed and successfully used in the asymmetric reduction of acetophenone. 1-Phenylethanol was obtained in 93% yield and 98% enantiomeric excess.

238


Scheme 3.6.5

3.6.3. Catalysts for C-C bond formation Lanthanide(lll) catalysts supported on ion exchange resins Lanthanide-mediated reactions have found extensive use in organic synthesis due to their high selectivities. Lanthanide triflates constitute recyclable Lewis acids tolerating aqueous reaction conditions and catalysing a variety of important organic reactions under mild conditions. Wang et al. studied the preparation and synthetic use of lanthanide(III) catalysts supported on ion

exchange resins. 52 A number of commercially available ion exchange resins were loaded with lanthanide(III) ions and their capacity of catalysing Mukaiyama aldol reactions has been tested. The reaction of benzaldehyde with a silyl enol ether in dichloromethane in the presence of Yb(III)loaded resin shown in Scheme 3.6.6 served as a model reaction for the classification of the different resins. In summary, it was found that strongly acidic ion exchange resins with large pores and surface area such as Amberlyst | XN-1010 or Amberlyst | 15 gave best results. Scheme 3.6.6

O

+ OS,Me3. "

OMe

TMSO O ~ O M e

OH O + ~

OMe

I

ii) l Reagents and conditions: i) Lanthanide(lll)resin,CH2CI2ii) ; TFA,CH2CI2 The reaction afforded a mixture of free hydroxyl aldol derivative and silylated product, easily desilylated with TFA in dichloromethane, with overall yields ranging from 71-83% independently of the metal ion. Yb(IID on Amberlyst| XN-1010 has been used ten times consecutively in this type of aldol reaction without any loss of catalytic activity.

239


Lanthanide(III) on ion exchange resins catalyse Mukaiyama aldol reactions in aqueous media, acetalisations, additions of silyl enol ethers to imines, aza-Diels-Alder reactions and the ringopening of epoxides with alcohols as depicted in Scheme 3.6.7. Scheme 3.6.7

[ ~

OTMS

+

(CH20)n

Yb-Amberlyst| 15 ~THF/water 4:1

r,,,,",,~ O ['-,.I"1"--.tOH (82%)

~

CHO

Br" ~

+

HC(OMe)3

Yb-XN 1 0 1 0

CH2CI2

,,-

OMe ~ O M e Br" v (100%)

,•__L 0

SnMe3 170

Reagents and conditions: i) Bpoc-OPh, KH; ii) a) KH, b) tBuLi, 3-butenylchlorodimethylsUane;iii) a) nBuLi, b) tBuLi, c) Me3SnCI;iv) 9-BBN, then H202; v) cyanomethyl 4-hydroxyphenoxyacetate,PPh3,DEAD

292

4.2. Multigeneration assembly strategies using traceless linkers

The stannane was introduced using the directed ortho-metalation reaction followed by addition of lrimethyltin chloride to give 168. Hydroboration of arylstannane 168 with 9-BBN and oxidative work-up with basic peroxide provided the primary alcohol 169. Mitsunobu reaction of this alcohol with the cyanomethyl ester of 4-hydroxyphenoxyacetic acid afforded preactivated ester derivative 170 in good yield (Scheme 4.2.1). Solid-phase synthesis was initiated with acylation of 170 onto (aminomethyl)polystyrene resin using DMAP and DIEA to give 171. A synthetic sequence analogous to the one described in Scheme 4.1.7 afforded 1,4-benzodiazepines 172 linked to the solid support. The aryl-silicon bond

was then cleaved in the f'mal step with anhydrous HF, delivering benzodiazepines 173 in good yields (Scheme 4.2.2). Scheme 4.2.2

Furthermore, to obtain a linking element that could be easily cleaved with trifluoroacetic acid, thus avoiding the need of using highly toxic HF, the same research group investigated a similar linker strategy based on germanium. 81 The synthesis of the appropriately functionalised germaniumlinked resin is shown in Scheme 4.2.3. Protection of 4-bromoaniline 166 as the 2-(4-methylphenyl)isopropyl carbamate (Mpc group) and sequential deprotonation, lithium-halogen exchange and trapping of the aryl anion with

293

4. Convergent assembly strategies on solid supports

chlorodimethyl{6-[(triethylsilyl)oxy]hexyl}germane

gave

silyl

ether

174.

The

directed

orthometalation reaction was used as before to introduce the trimethyltin group to give 175. Removal of the silyl group with TBAF afforded alcohol 176 that was allowed to react with cyanomethyl (4-hydroxyphenoxy)acetate under Mitsunobu conditions to afford preactivated ester 177. (Aminomethyl)polystyrene resin 29 was then directly acylated with 177 in NMP to give resin 178. Scheme 4.2.3

Br

. ••NH2 166

.j~NHMpc i), i i )

-

T e S O ~ G

e

/ \

174

Reagents and conditions: i) Mpc-OPh, KH; ii) KH, then tBuLi, 6-(TesO-hexyi)-Me2GeCI;iii) a) nBuLi, b)

tBuLi, c) Me3SnCI; iv) TBAF, THF, 5 min; v) cyanomethyl 4-hydroxyphenoxyacetate, PPh3, DEAD, THF The solid-phase route to germanium-linked benzodiazepines has been described before (Scheme 4.1.7), except for the carbamate deprotection of the Mpc group. While treatment of silyl-linked

180 with 3% TFA caused no detectable 2-aminobenzophenone cleavage from the resin, 181 showed less stability under acidic conditions. Cleavage of the Bpoc carbamate (as in the silicon

294

4.2. Multigenerationassembly strategies using traceless linkers

linker system), produced more than 10% cleavage of 2-aminobenzophenone under a variety of acids and reaction times. The use of a Mpc carbamate group as protecting group (which cleaves four times faster) brought the amount of undesired cleavage to less than 5%. In addition, treatment of 181 with the Lewis acid B-chlorocatecholborane and 0.5 equivalents of DIEA resulted in a fast and clean deprotection without any undesired 2-aminobenzophenone cleavage. Next, acylation of the aniline, Fmoc deprotection, cyclisation and alkylation afforded resin-bound germanium-linked benzodiazepines 184 which were cleaved from the solid support by treatment with neat TFA at 60~

to afford fully functionalised benzodiazepine derivatives 185. In addition, electrophilic

cleavage of the germanium-linked benzodiazepines 184 was investigated. Thus, it was found that treatment of 184 with elemental bromine for 5 min afforded bromobenzodiazepines 186 through cleavage of the germanium-aryl bond without detectable overbromination (Scheme 4.2.4). By using the germanium route, numerous functional groups, e.g. amides, esters, acids, phenols, acetals, acids and halides were tolerated. In addition, the ease of electrophilic demetalation, makes this route a significant improvement over the silyl method for traceless 1,4-benzodiazepine synthesis. Scheme 4.2.4

Reagents and conditions: i) R1-COCI, Pd2dba3-CHCI3, K2CO3, DIEA,THF; ii) 3% TFA in CH2CI2 (for 180); iii) B-chlorocatecholborane/DIEA (2:1), CH2CI2 (for 181); iv) TFA, 60~ 24h; v) Br2 (4 eq), CH2CI2

295


4.2.2. Synthesis of furans A traceless linker strategy for the synthesis of functionalised furans based on mesoionic isomiinchnones generated on solid support, was developed by Gallop et al. 82 The key step of this protocol takes advantage of an efficient [3+2] cycloaddition reaction with electron deficient acetylenes, followed by a thermally promoted cycloreversion reaction. 83-87 As shown in Scheme 4.2.5,

TentaGel|

resin was primarily acylated with different carboxylic acids using

diisopropylcarbodiimide (DIC) in the presence of catalytic amounts of DMAP. Conversion of amide 187 to imide 189 was accomplished by treating the resin twice with a 1:1 (v/v) mixture of malonyl chloride 188 in benzene at 60~

Quantitative diazo-transfer reaction to diazoimide 190

was effected at room temperature using tosyl azide in CH2C12/Et3N. Optimisation of this reaction sequence was facilitated by using gel-phase 13C-NMR, monitoring these transformations with initially acetylated resin with 2-13C-labeled Ac20. 88 The analysis indicated that both the imide and diazoimide formation proceeded with >95% conversion. Scheme 4.2.5

Reagents and conditions: i) DIC, DMAP, DMF; ii) 188, benzene, 60~ iii) TsN3, Et3N, CH2CI2, 18h

Resin-bound diazoimides 190 were subsequently reacted with different electron deficient acetylenes 191 in benzene at 80~ for 2 hours in the presence of Rh2(OAc)4 as a catalyst. Analysis of the crude products showed exclusively the presence of the desired furans 192 and excess unreacted acetylene, which, when sufficiently volatile (e.g propiolate esters), were eliminated in vacuo to provide furans of high purity. To avoid contamination of the desired furan product with

residual, non-volatile acetylene, a two step sequence was implemented for the cycloaddition reaction. Thus, ~3C-labelled diazoimide 193 was allowed to react with a large excess (10 eq) of dimethyl acetylenedicarboxylate (DMAD) 194 in the presence of Rh2(OAc)4 at room temperature in anticipation of trapping the bicyclic intermediate 196 on the polymeric support. After washing the

296


beads in order to remove excess acetylene, resin 196 was suspended in fresh solvent and heated to 80~ to promote cycloreversion. HPLC analysis of the crude product from this reaction showed the presence of pure furan 197 with neither starting acetylene nor other impurities being observed. Resin washings did not contain any 13C label, indicating that no cycloreversion occurred at room temperature, while gel-phase ~3C NMR of the resin after thermolysis showed no resonances from enriched carbons and suggested that cycloaddition to the polymer-bound isomiinchnone 195 proceeded efficiently at room temperature (Scheme 4.2.6). Scheme 4.2.6

Reagents and conditions: i) Rh2(OAc)4, benzene, 80~

ii) Rh2(OAc)4, benzene, r.t.; iii) benzene, 80~

The stepwise (room temperature/thermal) cycloreversion sequence failed to provide furans from acetylene derivatives activated by just a single electron withdrawing moiety (e.g. propiolate esters). These derivatives, less reactive than DMAD, did not undergo cycloadditions to the immobilised dipoles at an appreciable rate at room temperature.

297


To further illustrate the utility of this solid-phase synthesis, a small (32 member) combinatorial library of furans was generated via split synthesis by using the stepwise cycloaddition sequence. From eight carboxylic acids, two malonyl chlorides and two acetylenes, a library of four pools comprising eight compounds each was synthesised.

4.2.3. Synthesis of prostaglandins Based on a modification of the Noyori prostaglandin synthesis, Ellman et al. 89-91 developed a solid-phase synthesis of this interesting class of carbocycles (Scheme 4.2.7). Thus, after addition of alkylzinc reagents 202 to resin-bound 4-hydroxy-2-cyclopentanones 201, alkylation was carried out with alkyl triflates 203. This synthesis was originally performed with the DHP linker, but the cleavage conditions were not compatible with the target molecule. Due to the severe reaction conditions employed for coupling, the hydroxycyclopentane 199 had to be protected with the dimethoxytrityl group when using silyl linker 198. Scheme 4.2.7

Me2Z ~

r

~

~

TfO /

~

.

OTES 202

203

Reagents and conditions: i) Nail, DMF, r.t., 4 h; ii) a) 3% CI3CCOOH in CH2CI2,

b) PDC, DMF, 40~

3h; iii) a) 202, THF, -78~ to r.t., b) 203, THF, -78~

iv) a) L-Selectride,-78~

298

b) 1M TBAF, THF, r.t., 3h

lh;


After two reaction steps, the prostaglandin 204 was isolated in a yield greater than 50% as a single diastereoisomer. Furthermore, the alkylation reaction on the MerrifieM resin gave only poor results. A macroporous resin proved to be more appropriate for this reaction sequence. On the other hand, it is well known in prostaglandin chemistry that the lack of reactivity of the initially formed enolate as well as the danger of proton exchange and subsequent elimination of the alkoxy group can lead to the corresponding cyclopentenone. To overcome this problem, Ellman et al. introduced an alternative solid-phase prostaglandin synthesis. As shown in Scheme 4.2.8, a

resin-bound iodocyclopentenone 205, formed in three steps from 200, was treated with an organoborane under palladium catalysis. Subsequent Michael addition of a vinyl cuprate led to the introduction of the co side chain. Analogous chemical manipulations as described before afforded prostaglandins 206. Scheme 4.2.8

Reagents and conditions: i) R1-BBN, Pd(0), K2CO3; ii) vinyl cuprate; iii) L-selectride; iv) TBAF

299


4.3. Multicomponent assembly strategies with single functional group liberation 4.3.1. Synthesis of imidazoles Many biologically active therapeutic agents contain five-membered heterocycles. 92 The imidazole ring system is of particular interest since it is a component of histidine and its decarboxylation metabolite histamine. The wide applicability of the imidazole phannacophore can be attributed to its hydrogen bond donor-acceptor capability as well as its high affinity for metals which are present in many protein active sites (e.g. Zn, Fe, Mg). Furthermore, improved pharmacokinetics and bioavailability of peptide-based protease inhibitors have been observed by replacing an amide bond with an imidazole. Based on a four component condensation reaction (the Ugi reaction93), Mjalli et al. 94 developed a solid-phase protocol for the synthesis of tetrasubstituted imidazoles. Because of the limited number of commercially available isocyanides, the selected strategy started with the generation of an isocyanide component tethered to Wang resin. Scheme 4.3.1

Reagents and conditions: i) Ph3P, CCI4, Et3N, CH2CI2; ii) arylglyoxals 210, R1-NH2, R2-COOH;

iii) NH4OAc, AcOH, 100~ iv) 10% TFA in CH2CI2 300

4.3. Multicomponentassembly strategies with singlefunctional group liberation

A series of N-formylated aliphatic amino acids 95 207 were subsequently attached to the Wang resin as shown in Scheme 4.3.1, affording 208. Dehydration of 20896 provided resin-bound isocyanides 209 quantitatively as shown by 1H-NMR of the resin. Multicomponent condensation of resin 209 with arylglyoxals 210, primary amines and carboxylic acids afforded resin-bound ct(N-acyl-N-alkylamino)-13-ketoamides 211 that were further reacted with a large excess of NH4OAc in AcOH to give immobilised imidazoles 212. Final cleavage with 10% TFA provided imidazoles 213. The length of the isocyanide linker, the electronic nature of the aryl glyoxals, the use of different primary amines (with exception of aniline), as well as the use of both aliphatic and aromatic carboxylic acids, showed no effect on the yield of the imidazoles 213. Extension of this synthetic protocol was further investigated by Sarshar et al. 97 by attaching the aldehyde or amine component to the Wang resin. Hence, functionalised polymers 215 and 217 were prepared by standard coupling methods of carboxybenzaldehyde 214 and N-Fmoc-6aminohexanoic 216, respectively. Resin 219 was prepared via a modified Mitsunobu coupling of 4-hydroxybenzaldehyde 218 to Wang resin 84 (Scheme 4.3.2). Scheme 4.3.2

Reagents and conditions: i) DIC, DMAP, THF, 23~ 48h; ii) DIC, DMAP, CH2CI2,23~

24h; iii) 20%

piperidine, DMF; iv) N-ethylmorpholine, DIAD, Ph3P, sonicate for lh, then stir at 23~

16h.

301


The protocol for the preparation of solid supported imidazoles 220 and 221 involved the condensation of resins 215 or 217 with a large excess of 1,2-dicarbonyl compounds, NH4OAc and primary amines or aldehydes. Imidazoles of type 222 were prepared in a similar manner by replacing primary amines with NHnOAc. Following resin cleavage with 20% TFA afforded imidazoles 223, 224 and 225 in high yields and purities (Scheme 4.3.3). Scheme 4.3.3

0

N..--{R3(4)

HO~ " ~

R1

?

x " ~ " ~ N~'" R 3 ( 4 ) . o ~ N " - ~

223

N'~R4(3 )

I~N\~>""R4(3)

R3(4 )x,j,....~Na 4(3) 224

' R2

"O 225

4.3.2. Synthesis of proline derivatives By using a three component 1,3-dipolar cycloaddition reaction, 98 Hamper et al. 99 developed a solid-phase synthesis of highly substituted pyrrolidines via resin-bound azomethine ylides. As shown in Scheme 4.3.4, several substituted hydroxybenzaldehydes 226 were attached to Wang resin 84 via an alkylaryl ether linkage through a Mitsunobu reaction to give 227. These polymer-supported aldehydes were allowed to react with an a-amino ester 228 and maleimide

229 in DMF to give immobilised proline analogues 230 that were liberated from the resin by treatment with 50% TFA to afford 231. The dipolar cycloaddition provided mixtures of diastereoisomers, which could be separated by HPLC.

302

4.3. Multicomponent assembly strategies with singlefunctional group liberation

Scheme 4.3.4

Reagents and conditions: i) Ph3P, DEAD, THF; ii) DMF, 80-100~

iii) 50% TFA in CH2CI2

4.3.3. Synthesis of 2-arylquinoline-4-carboxylic acid derivatives 2-Arylquinoline-4-carboxylic acids and derivatives were shown to possess a wide variety of biological effects as antimalarial, antimicrobial, antitumor, antioxidants and cardiovascular agents. 1~176 In addition, other derivatives have recently been shown to be potent tachykinin NK3 receptor antagonist 1~ or to exhibit analgesic activity, lo2 Based on a multi-component condensation approach related to the Doebner reaction, lo3 Gopalsamy et al. 1~ developed a solid-phase synthesis for this clinically useful pharmacophore. Thus, starting

from Rink resin 65, acylation with the required N-Fmoc-amino acid 232 and deprotection with piperidine gave the polymer-supported amine 233 (90% yield) which was acylated with pyruvyl chloride (234). Immobilised pyruvic amide 235 was refluxed with excess of preformed benzylidene aniline 239 or alternatively condensed with an excess of an equimolecular mixture of aldehyde 236 and anilines 237. Cleavage of 238 with 45% TFA afforded compounds 240 in good yields and with high purifies (>90%) (Scheme 4.3.5).

303


Scheme 4.3.5

Reagents and conditions: i) HOBt, HBTU, DIEA, DMF, then 20% piperidine in DMF; ii) CH2CI2,py, 0~

iii) 235, benzene, 80~ 8h; iv) 50% TFA in CH2CI2

Although electron-withdrawing groups in the aldehyde building-block improved the overall yield, the reaction proceeded well for benzaldehyde. Furthermore there was no significant effect on the cyclisation by varying the amino acid employed.

4.3.4. Synthesis of dihydropyrimidines The Biginelli dihydropyrimidine synthesis 1~176 is another relevant multicomponent condensation reaction that has been recently adapted to the solid phase by Wipfet al. 1~ to prepare a small library of this interesting pharmacophore. In fact, many examples of this class of N-heterocycles have been shown to display a wide range of biological effects as for instance antiviral, 1~ calcium channel blocking,

109

or antihypertensive activity. 11~

In this sequence, ),-aminobutyric acid derived urea 241, prepared from GABA and KOCN in H20/THF, 111 was attached to Wang resin 84 to provide 242 in high yield. Subsequent

304

4.3. Multicomponent assembly strategies with singlefunctional group liberation

multicomponent Biginelli condensation with excess of [3-ketoesters 243 and aldehydes 244 in the presence of a catalytic amount of HC1 afforded immobilised dihydropyrimidines 245 which, after cleavage of the benzyl ester group with 50% TFA, provided dihydropyrimidines 246 (Scheme 4.3.6). Scheme 4.3.6

Reagents and conditions: i) EDCI, DMAP, DMF, r.t., 24h; ii) THF/conc. HCI (4:1), 55~

36h; iii) TFA, CH2CI2

The individual products 246 were obtained in high yields and excellent purity (>95%). Since [3oxoesters 243 are readily obtained in one step and many aldehydes 244 are commercially available, this reaction is applicable to the parallel synthesis of large compound libraries. The GABA-derived acid linker increases the water solubility of the products and offers a convenient handle for additional functionalisation.

305


4.4. Multigeneration assembly strategies with cyclisation-assisted cleavage 4.4.1. Synthesis of 1,4-benzodiazepine.2,5-diones Featuring a cyclisation-assisted cleavage strategy (cf. Chapter 1.7), first described by Camps et al., 112 Mayer eta/. 113 developed a solid-phase synthesis of 1,4-benzodiazepinediones. Scheme 4.4.1

O

R2

N"

253 Reagents and conditions: i) DIC, DMF, then 249 (route A), 248 (route B); ii) 20% piperidine in DMF;

iii) 2M SnCI=in DMF, 5h; iv) NaOtBu, THF, 60~ 24h

As outlined in Scheme 4.4.1, starting from commercially available Fmoc-amino acid derivatised Wang resins 247, or those prepared by known loading procedures, deprotection with 20%

306

4.4. Multigenerationassemblystrategies with cyclisation-assistedcleavage

piperidine in DMF and coupling with o-nitrobenzoic acids 248 or protected o-anthranilic acids 249 afforded immobilised derivatives 250 (route A) and 251 (route B). Fmoc deprotection (route A) or reduction of the nitro group (route B) gave quantitatively polymer-bound amido-anthranilate 252 as determined by TFA cleavage of a small sample of intermediates 251 and 25 2. The option of using either synthon within the reaction sequence permits a wider range of aromatic substituents to be incorporated than would otherwise be possible through a single route. Cyclisation of the common aminoamide intermediate 252 with concomitant release from the support furnished the desired 1,4-benzodiazepin-2,5-diones 253 in high yields and excellent purifies. Optimal basepromoted cyclisation results were obtained by heating the resin precursor in THF with sodium tertbutoxide (Scheme 4.4.1).

4.4.2. Synthesis of benzoisothiazolones The Parke-Davis research group developed a solid-phase synthesis of benzoisothiazolones 258, 47 which are known for their antibacterial, antimycotic and antifungal properties. 114 As outlined in

Scheme 4.4.2, aromatic thiocarboxylic acids 254 were tethered to the MerrifieM resin in the presence of Et3N to form polymer-bound thioethers 255. Conversion into active esters by the BOP group followed by treatment with different amines and hydrazides yielded the corresponding immobilised amide derivatives 256. Oxidation of the sulfide link to the corresponding sulfoxide 257

and activation with trichloroacetic anhydride led to the expected ring closure with

simultaneous release of the product benzoisothiazolones 258 in up to 60% yield in a Ptunmerertype rearrangement. The oxidative key step to the sulfoxide 257 provided an interesting problem. In solution, this activation can be accomplished using a stoichiometric amount of oxidant to avoid over oxidation to the sulfone. In practice, it is difficult to control the reagent-to-starting material ratio in solid-phase organic synthesis. Generally, the possibility to use a large excess of reagent and to remove it easily, is considered as an advantage of the solid-phase synthesis method. After a survey of several potential oxidants for selective oxidation of sulfides to sulfoxides, N-(phenylsulfonyl)-3phenyloxaziridine (Davies reagents) was selected as the reagent of choice. Selective monooxidation was achieved by limiting the reaction time and removal of excess reagent.

307


Scheme 4.4.2

Reagents and conditions: i) 0.4 M Et3N in dioxane, 96h; ii) N,N-carbonyldiimidazole, dioxane,

DIEA, then R2-NH2; iii) 0.13 M NaBrO2 in dioxane/H20 (8:1), or N-(phenylsulfonyl)-3phenyloxaziridine), CHCla; iv) trichloroacetic anhydride, CH2CI2, 0~

4.4.3. Synthesis of pyrazolones An efficient and general method to prepare diverse [3-ketoesters linked to a solid support was developed by Tietze et al. using readily available acid chlorides 259 and haloalkanes as building blocks. The obtained polymer-bound 1,3-dicarbonyl compounds served as substrates toward the preparation of a library of substituted pyrazolones, which are well known for their widespread biological activity as analgesics, antipyretics, antiphlogistics, antirheumatics, antiarthritics and uricosurics. 115 Using solution chemistry, reaction of acid chlorides 259 with Meldrum's acid 260 in the presence of pyridine gave the corresponding acyl Meldrum's acid 261 almost quantitatively. Heating an excess of 261 with the spacer-modified polystyrene-resin 26252 afforded polymer-bound [3ketoesters 263 with concomitant release of carbon dioxide and acetone. The reaction could easily be monitored by FT-IR spectroscopy of the resin (KBr-pellet), showing in every case a strong appearence of the characteristic carbonyl stretching of [~-ketoesters. Selective alkylation of the o~position,, of 263 to afford resin-bound 264, was achieved at room temperature using a large excess of haloalkanes in the presence of TBAF (Scheme 4.4.3).

308

4.4. Multigenerationassembly strategies with cyclisation-assistedcleavage

Scheme 4.4.3 0

RI-"~CI

i)

0

0 259

O•

H

R1

/~--0 0

260

261

Reagents and conditions: i) py, CH2CI2, 0~ - r.t.; ii) THF, reflux iii) R2-X, TBAF, THF, 25~ - 66~

By following the above described reaction sequence, a set of immobilised I]-ketoesters of type 264 were synthesised and directly used to prepare a collection of 1-phenylpyrazolones 266. Thus, addition of a large excess of phenylhydrazine in the presence of trimethylorthoformate as dehydrating agent afforded polymer-bound phenylhydrazones 265. Cyclisation of 265 with concomitant release of the 3,4-disubstituted-N-phenylpyrazolones 266 was accomplished by mild acidic treatment with 2% TFA in good overall yields and excellent levels of purity (Scheme 4.4.4). Scheme 4.4.4

R2

R1

I

Ph 266

Reagents and conditions: i) phenylhydrazine, THF, trimethylorthoformate, r.t.-ii) 2% TFA in MeCN, r.t.

309


Alternatively, y-alkylation of polymer-bound acetoacetate 267116 provided the starting materials 268 for the synthesis of 3-substituted-N-phenylpyrazolones 269 via cyclisation-assisted cleavage (Scheme 4.4.5). Scheme 4.4.5

iii)

eh,

N-N

D2

R1

269 Reagents and conditions: i) LDA, RI-X; ii) nBuLi, R2-X;

iii) a) phenylhydrazine, THF, r.t., 3h, b) toluene, 100~

4.4.4. Synthesis of hydantoins Hydantoins have been reported to possess a wide range of biological activities as anticonvulsants, antiarrythmics and antidiabetics. Herbicidal and fungicidal activities have also been noted. 117 In a solid-phase synthesis aproach of hydantoins developed by the Parke-Davis group 47 different Cterminally coupled amino acids 270 were first deprotected and then treated with different isocyanates to give resin-bound ureas 271. Heating of 271 in 6N hydrochloric acid allowed cyclisation with simultaneous cleavage from resin, affording hydantoins 274. To achieve a greater diversity in the products, the amino acids may be reductively alkylated with aldehydes prior to reaction with the isocyanates (Scheme 4.4.6). Dressman et al. 118 described an alternative solid-phase synthesis in which the amino acids were N-

terminally linked to a hydroxymethyl resin through a carbamate linker. Amide formation gave products 273 which, after treatment with base cyclised to yield hydantoins of type 274 (Scheme 4.4.6).

310

4.4. Multigeneration assembly strategies with cyclisation-assisted cleavage

Scheme 4.4.6

Reagents and conditions: i) R4-NCO,DMF, 6h; ii) 6 N HCI, 100~

2h;

iii) R4-NH2, DCC, HOBt, DMF, r.t., 24h; iv) Et3N, MeOH, 48h

In a similar approach, Kim et al. 119 coupled N-Fmoc protected amino acids 275 to the Wang resin 84 under standard conditions and, after deprotection, reductively alkylated the free amino group using different aldehydes and NaBH3CN to give polymer-bound amines 277. Reaction with different

isocyanates provided

immobilised

ureas

278.

Upon

treatment

with

neat

diisopropylamine, hydantoin derivatives 274 were rapidly formed with simultaneous cleavage from the resin in high yields and purities (Scheme 4.4.7).

311


Scheme 4.4.7

Reagents and conditions: i) DIC, DMF, DMAP, 12h; ii) 20% piperidine, DMF, 1h; iii) R3-CHO, DMA, 1% AcOH, 5h, then NaBH3CN; iv) R4-NCO, DMF/toluene (1:1);

v) neat diisopropylamine, r.t., lh

4.4.5. Synthesis of 5-alkoxyhydantoins A protocol for the solid-phase synthesis of 5-alkoxyhydantoins 283 incorporating three sites of functional diversity on the hydantoin nucleus was developed by Hanessian et al. 120 After optimisation of the synthetic sequence in solution, the protocol was extended to the solid support. Thus, the cesium salts of o~-hydroxy acids (279) were linked to the Merrifield resin to give polymer-bound tx-hydroxyesters 280 which were efficiently transformed into the corresponding N-benzyloxyamino esters 281 by treatment with uifluoromethanesulfonic acid anhydride in the presence of lutidine, followed by in situ addition of O-benzylhydroxylamine. Condensation of 281 with different individual aryl isocyanates gave immobilised ureas 282. Treatment of 282 with potassium tert-butordde in an alcoholic solution led to sequential cyclisation and detachment from the polymer to give in high purities the desired 5-alkoxyhydantoins 283 via an elimination-addition mechanism (Scheme 4.4.8).

312

4.4. Multigeneration assembly strategies with cyclisation-assistedcleavage

Scheme 4.4.8

8h; ii) (CF3SO2)20, lutidine,CH2CI2, -78~ - 0~ iii) BnONH2, 0~ iv) Ar-NCO, 1,2-dichloroethane, reflux, 24h; v) KOtBu, R2-OH, r.t.

Reagents and conditions: i) DMF, 80~

4.4.6. Synthesis of 1,3-disubstituted quinazolin-2,4-diones When seeking compounds with activity in the central nervous system (CNS), one has to consider that highly polar functional groups generally prevent molecules from easily crossing the bloodbrain barrier. On the other hand, it is known that the quinazolinedione core structure occurs in a large number of bioactive compounds including serotonergic, dopaminergic and adrenergic receptor ligands and inhibitors of aldose reductase, lipoxygenase, cyclooxygenase, collagenase and carbonic anhydrase. A library based upon this structure would therefore be expected to provide lead compounds in a wide range of bioassays. Taking into account these arguments, Smith et al. 121 aimed to develop a solid-phase approach to 1,3-disubstituted quinazolinediones which would not leave an extraneous polar resin-tethering substituent on the resulting molecules which might compromise CNS penetration. Thus, as outlined in Scheme 4.4.9, a chloroformate-functionalised polystyrene resin 284 was treated individually with a wide range of anthranilic acid derivatives 285 in the presence of Hiinig's base to give the urethane-linked system 286. Structurally diverse primary amines were

readily coupled to the free carboxylic acid of 286 using standard PyBOP conditions to give anthranilamides 287. Thermal treatment of 287 caused the amide nitrogen to cyclise onto the 313


urethane to generate, with concomitant resin release, heterocycles of type 288 lacking any additional tethering substituents and with very high levels of purity (usually higher than 95%). Scheme 4.4.9

0

N,.R2 ~i ~ N R H 1

X~

0 iii)

"

~ ~ N

"R2

~,~N.~

287

0

288

Reagents and conditions: i) DIEA, CH2CI2,r.t., 1h; ii) R2-NH2(3 eq), PyBOP;iii) DMF, 125~

16h

Whilst there are several commercially available anthranilic acids of type 285, much greater structural diversity can be achieved if the substiuents at N-1 in 286 could be incorporated from primary amines 29t}. Using a modified literature procedure 122 a number of different anthranilic acid derivatives of type 285 were synthesised (Scheme 4.4.10) and incorporated in the above described protocol. Scheme 4.4.10

~ 289

314

COOH CI

+

R1-NH2 290

K2CO3 / CuBr (cat.)

~ ~ 1 ~ COOH

DMF, 150~ lh.

NH R1 285

4.4. Mulfigeneration assembly strategies with cyclisation-assisted cleavage

4.4.7. Synthesis of pyrazolo[l,5-a]pyrrolo[3,4-d]pyrimidinediones In a further example where cleavage is induced during final cyclisation step, DeWitt et al. 47 developed a solid-phase protocol for the synthesis of tricyclic systems of type 295 which in addition are known to be inhibitors of cholesterol-O-acetyltransferase. Thus, as depicted in Scheme 4.4.11, starting from acrylic acid substituted resin 291, polymerbound pyrrolidinones 292 were easily prepared by sequential Michael addition of amines followed by cyclisation with diethyloxalate. After substitution reaction with different 3-aminopyrazoles at 100~ subsequent treatment with 5N HC1 at 80~ afforded with concomitant cleavage from the resin, the corresponding pyrazolopyrrolopyrimidinediones 294. Additional molecular diversity could be introduced by alkylation of the liberated compounds 294 in solution to give 295. Scheme 4.4.11

295 Reagents and conditions: i) R1-NH2,DMF, r.t., 24h; ii) (EtOOC)2, Na2CO3, DMF, 60~ 2h;

iii) AcOH, 100~ 2h; iv) R3-X,K2CO3,DMF, 60~ 2h

315


4.4.8. Synthesis of quinazolinones 3H-Quinazolin-4-ones of type 300/301 represent interesting pharmacophores displaying a wide range of biological properties. 123-125 Therefore, the development of efficient strategies for the combinatorial and parallel synthesis on solid support of this interesting target allowing the introduction of a high degree of molecular diversity has attracted considerable attention. 126 One example of a successful application of solid-phase chemistry constitutes the highly versatile synthesis of quinazolinones 300/301 which efficiently combines an aza-Wittig reaction with a multidirectional cyclisation cleavage. Iminophosphoranes were shown to be useful intermediates in organic synthesis, particularly for the preparation of different heterocyclic systems containing an endocyclic C,N double bond. In these cases, an aza-Wittig-mediated anellation reaction was involved as the key step. 127-129 Scheme 4.4.12

[~

0 COOH

i) ~

~NaO

ii) _

N3

296

297

Reagents and conditions: i) Merrifield resin (3.4 mmol/g), Cs2CO3, DMF, KI, 80~

8h; ii) Ph3P (1M in THF), r.t., 6h; iii) R-N=C=O, CH2CI2,r.t., 8h; iv) RI-XH, THF, 50~ 4h

Alkylative esterification of 296 via the corresponding cesium salt 130 with highly loaded Merrifield resin (3.4 mmol/g) resulted in polymer-bound o-azido ester 297.131,132 Treatment of 297 with a fivefold excess of PPh 3 in THF

316

at room temperature produced the corresponding

4.4. Multigeneration assembly strategies with cyclisation-assisted cleavage

iminophosphorane 298 attached to the resin (evolution of N2was clearly detected). Partitioning of the beads and subsequent aza-Wittig reaction with different isocyanates at room temperature smoothly formed the corresponding reactive carbodiimides 299. Additional partitioning and treatment with different nucleophiles (e.g. amines, thiols) led, via intramolecular cyclisation and simultaneous cleavage from the resin, to quinazolines 300 (and/or 301 when primary, nonsterically hindered amines were used) in good yields and excellent purities (>97%) (Scheme 4.4.12). The formation of the polymer-bound compounds was routinely monitored by FT-IR of the resin beads. The product composition 300:301

was strongly influenced by differences in

nucleophilicity and/or steric hindrance. When those differences were minimal, both possible compounds 300 and 301 were generally formed in 1:1 ratio.131,132

317


4.5. Multicomponent assembly strategy with cyclisation-assisted cleavage 4.5.1. Synthesis of diketopiperazines The diketopiperazine scaffold proved to be a versatile template in combinatorial chemistry due to four ring atoms which can be centers for the generation of molecular diversity. 133 Based on the Ugi four component condensation reaction of a polymer-bound amino acid, followed by

cyclisation-assisted cleavage, Chucholowski et al. 132 developed a novel solid-phase synthesis that allows the generation of diketopiperazine libraries with four centers of diversity. As outlined in Scheme 4.5.1, Rink amine resin was charged with a Fmoc protected amino acid to afford after

deprotection amines 303. Next, the resin-bound amino acid was divided into separate reaction vessels and the Ugi reaction was performed treating each vessel individually with an aldehyde, an isocyanide, and an Fmoc-protected amino acid 134 to afford 304. Deprotection of the Fmoc group under standard conditions to give dipeptides 305 and subsequent warming up in dioxane, resulted in cyclisation-assisted cleavage and concomitant release of very pure diketopiperazines 306.135 Although diketopiperazines 306 were obtained with very high levels of purity, the yields of isolated material were only moderate, probably due to the alternative cyclisation mode leading to resin-bound 307. Scheme 4.5.1

Reagents and conditions: i) 20% piperidine/DMF, r.t.; ii) TPTU, Fmoc-NHR1CHCO2H, DIEA, DMF, r.t.;

iii) RaCHO, R3NC, Fmoc-NR4CHCO2H, dioxane/CH2ClflMeOH (4:1:1); iv) dioxane, 102~

318

4.6. Multigeneration assembly strategies with multidirectional cleavage

4.6. Multigeneration assembly strategies with multidirectional cleavage 4.6.1. Without activation of the linker moiety 4.6.1.1. Synthesis of ketoureas The concept of introducing additional molecular diversity while liberating final compounds from the resin was used by DeWitt et al. 47 by employing resin-bound Weinreb amides. 136 Hence, simple bifunctional templates were derivatised on solid support to produce a library of ketoureas of type 312. Thus, as outlined in Scheme 4.6.1, Kornblum oxidation with sodium hydrogen carbonate in DMSO converted the Merrifield resin into a support-bound benzaldehyde 308, which gave an O-methylhydroxylamine resin 309 by heating with hydroxylamine and subsequent reduction with cyanoborohydride. Coupling with different N-Boc protected aminobenzoic acids 310, deprotection and reaction with different isocyanates afforded the corresponding ureas 311. Treatment of 311 with different alkyl- and arylmagnesium bromides led, via nucleophilic attack, to cleavage of ketoureas 312 from the resin. Scheme 4.6.1

Reagents and conditions: i) NaHCO3, DMSO, 155~ 20h; ii) a) MeONH2, py, EtOH, 80~ b) NaBH3CN,

EtOH, HCI, r.t., 3h; iii) DIEA, BOP, then TFA; iv) R2NCO;v) R3MgX,THF, CH2CI2,-78~ to -10~ 2h

319


4.6.1.2.

Synthesis

of

bicyclo[2.2.2]octanes

Employing enolate chemistry, Ley et al. z37 developed a solid-phase synthesis of bicyclo[2.2.2] octanes of type 316 based on a double Michael addition strategy. As depicted in Scheme 4.6.2, polymer-bound acrylate 313 was treated with cyclohexenone enolates derived from 314 to give 315. After reductive amination, resin-bound bicyclo[2.2.2]octanes 316 were cleaved under a set of different conditions. Aminolysis with different amines and acidolysis using TFA led to the formation of 317 and 318, whereas reduction with DIBAH gave alcohols of type 319. Since more than 250 different acrylates and enones are currently commercially available and the number of amines available for reductive amination is enormous, this synthetic sequence offers great potential for the synthesis of a highly diverse library. Scheme 4.6.2

O -OH iii)

R3~.Nf'i~3

-

317

O~.- NHR 4

2 R3Nf-

iv)

-316

R 1t/,'~2 R3.~Nf

-

R,.~::

v)

Reagents and conditions: i) LDA, THF, -78~

R3~.N~.. ~

318

H 319

- r.t.; ii) (R3)2NH,Na2S04,NaBH(OAc)3, CH2CI2,AcOH" iii) TFA; iv) R4-NH2;v) DIBAH

320


4.6.1.3. Synthesis of cyclopentane and cyclohexane derivatives Based on a domino Knoevenagel/ene reaction, Tietze and Steinmetz 52 developed a stereoselective solid-phase synthesis of cyclopentane and cyclohexane derivatives of type 326 and 327 using a Merrifield resin modified with a propandiol linker 320 as shown in Scheme 4.6.3. Subsequent

reaction with monomethyl malonoyl chloride 321 afforded the polymer-bound malonate 322, which, in a two-component domino reaction was treated with unsaturated aldehydes 323 in the presence of a catalytic amount of piperidinium acetate and zinc chloride. Except for m-substituted aldehydes, the initial Knoevenagel condensation occurred without addition of dehydrating agents and the subsequent intramolecular ene reaction gave cyclopentane and cyclohexane derivatives 3 2 5 after cleavage from the resin either by reduction or transesterification.

Scheme 4.6.3

__/ MEMO ~"e o ""-0

327 Reagents and conditions: i) DIEA, CH2CI2, 0~ 2h; ii) PipOAc, CH2CI2, r.t.; iii) ZnBr2, CH2CI2, 3d;

iv) DIBAH, toluene, 0~ 12h; v) Ti(OEI)4, AcOEt, 80~ 3d

321


In either case the products were obtained in good yields, high purity and excellent levels of diastereoselectivity. Only modest diastereoselectivities were observed when geminally disubstituted aldehydes were used.

4.6.2. With activation of the linker moiety ("safety-catch" linkers)

4.6.2.1. Synthesis of arylacetic acids The development of general strategies for the formation of carbon-carbon bonds is of particular importance for the construction of small organic compound libraries. As an example, Ellman et al. 138 developed a solid-phase synthesis of substituted arylacetic acid derivatives 335, 336 which represent an important class of cyclooxygenase inhibitors. As key steps for carbon-carbon bondforming reactions in this synthetic sequence, enolate alkylation 139 and palladium-mediated Suzuki cross-coupling 14~were selected. The acylsulfonamide linker developed by Kenner was selected as linkage that would be compatible with the basic enolate formation and the Suzuki reaction conditions, yet at the end of the synthesis labile enough for nucleophilic cleavage of the final products from the solid support. 141 Under basic conditions, the acylsulfonamide (pKa~2.5) is deprotonated, preventing nucleophilic cleavage. Once solid-support synthesis is completed, however, alkylation e.g. by treamaent with diazomethane results in the formation of the Nsubstituted derivatives that are activated for nucleophilic displacement. Thus, as shown in Scheme 4.6.4, starting from sulfonamide-derivatised support 329, readily prepared by treating aminomethylated resin with 4-carboxybenzenesulfonamide 328 under standard coupling conditions, trealment with the pentafluorophenyl ester of 4-bromophenylacetic acid 330 provided acylsulfonamide 331. Addition of excess LDA to 331 at 0~ gave the corresponding trianions which were treated with activated or unactivated alkyl halides to yield monoalkylated derivatives 332 (overalkylation to the bisalkylated products was minimal, and partial alkylation of the carboxamide group is irrelevant since the linker remains attached to the solid support after cleavage). In addition, the alkylated product is protected from cleavage under the basic reaction conditions since the acylsulfonamide remains deprotonated. A subsequent palladium-catalysed conversion with alkyl-9-BBN derivatives or alkylboronic acids under Suzuki conditions yielded the coupling products 333. Again, under the basic conditions employed deprotonation of the acylsulfonamide moiety prevented hydrolysis. Following rinsing of the resin with 5% TFA to ensure complete protonation and N-methylation of the sulfonamide linker with diazomethane gave 334, thus activating the linker moiety towards nucleophilic displacement. Cleavage from the resin with a series of reactive nucleophiles afforded products 336 and 3 37. Cleavage reaction with weaker nucleophiles such as aniline succeeded only when the acylsulfonamide was activated by cyanomethyl substitution 335.142

322


Scheme 4.6.4

Reagents and conditions: i) DMAP; ii) LDA, THF, 0~ then RI-X; iii) R2-B(OH)2, Pd(PPh3)4);

iv) CH2N2or BrCH2CN; v) R6-OH or R4RSNH

4.6.2.2. Synthesis of pyrimidines Pyrimidines are an interesting class of nitrogen-containing heterocycles which display a broad range of useful properties. 143,144Based on a novel cyclocondensation reaction between acetylenic ketones 145 of type 339 and polymer-bound isothiourea 338, Obrecht et al. 132 developed a versatile and efficient solid-phase synthesis of polymer-bound 2-(alkylthio)-4,6-disubstituted pyrimidines 340, and combined this protocol with the nucleophilic displacement reaction of the 2sulfonyl group of pyrimidines 146,147 as the key cleavage reaction. In addition, simple transformations of the pyrimidine nucleus allowed the preparation of structurally highly diverse pyrimidines. Thus, as outlined in Scheme 4.6.5, reaction of resin-bound thiouronium salt 148 3 38

323


with acetylenic ketones 339 in DMF in the presence of DIEA, followed by cleavage of the tertbutyl ester group with TFA, afforded the polymer-bound pyrimidine carboxylic acids 341) in high yields (as determined by cleavage of the 2-alkylsulfonyl moiety from the resin with pyrrolidine to give 341). Conversion of the carboxylic acid 340 into the corresponding pentafluorophenyl esters 342 or hydroxysuccinimide derivatives 343 under standard conditions proceeded smoothly. Partition of the resin beads and parallel treatment with different primary and secondary amines gave the polymer-bound pyrimidine amides 344. This reaction sequence could easily be followed by ATR-IR (attenuated total reflexion method). As a key step in this strategy, the 2-thioalkyl moiety was activated by oxidation with m-CPBA yielding the corresponding sulfones 345. Partitioning of the beads and multidirectional cleavage with different O-, N-, S-, and C-nucleophiles gave the final products 346 in high yields and excellent purities. This oxidation and cleavage protocol constitutes a novel type of safety-catch linker strategy 141 allowing the introduction of additional structural diversity onto the pyrimidine ring under simultaneous release of the final compounds 346. Scheme 4.6.5

Reagents and conditions: i) DIEA, DMF, r.t.; ii) 50% TFA, CH2CI2, r.t.; iii) EDCI, DMF, C6FsOH; iv) EDCI,

HOSu, CH2CI2;v) m-CPBA, CH2CI2;vi) pyrrolidine, dioxane, r.t.; vii) R1R2NH,CH2CI2;viii) YH, dioxane, 50~

324


In view of achieving the highest possible degree of molecular diversity, the developed solid-phase pyrimidine-assembly strategy was combined with the attractive features of multicomponent reactions. TM Thus, starting from the polymer-bound pyrimidine carboxylic acid 340 as the acid component, reaction with an excess of aldehydes, amines, and isocyanides afforded in an Ugi-type reaction 149 the corresponding resin-bound ~-(acylamino)amides 347. Oxidation to the corresponding sulfones 348 and cleavage with pyrrolidine led to the corresponding Ugi products 349 in good yields and excellent levels of purity (Scheme 4.6.6). Scheme 4.6.6

i)

R1 O

R3 N ~

N~

iP

340

R2

H

347 R1 O

iii)

NL ~NII~N~I~

R2

N

O

R3

H

ph

349 Reagents and conditions: i) R1-NH2, R2-CHO, R3-NC, (5 eq), dioxane/MeOH (4:1), 55~

48h;

ii) m-CPBA (3 eq), CH2CI2,r.t., 15h; iii) pyrrolidine (1 eq), dioxane, r.t., 6h

Scheme 4.6.7 o

YH

35O YH = R-NH2, R1R2NH, R-OH, R-SH, CH2(COOEt)2; Y = CN, N3.

325


One limitation encountered so far was the well known lack of reactivity of aromatic aldehydes and isonitriles under the Ugi conditions. The scope of this method was further extended by introduction of a third substituent at the 2-position of the pyrimidines. Thus, polymer-bound sulfones 348 were subjected to multidirectional cleavage with one equivalent of different nucleophiles affording compounds 350 in good yields and high purities 148 (Scheme 4.6.7). A similar approach towards the synthesis of pyrimidines was recently described by Suto et al. 15~ starting from polymer-bound thiol 351 as decribed in Scheme 4.6.8. Scheme 4.6.8

Reagents and conditions: i) NEt3, DMF, NovaSyn| TG Thiol resin (351); ii) m-CPBA, CH2CI2; iii) R1R2NH,

CH2CI2; iv) NaOH, H20, THF, then HCI, THF; v) oxalylchloride, CH2CI2;vi) R3-NH2,CH2CI2;vii) R4-NH2,CH2CI2; viii) NMM, CICOOiBu, THF; ix) NaBH4, H20, THF; x) PhOH, PPh3, DEAD, NMM

326


Treatment of 2-chloropyrimidine 352 with NovaSyn~I'G thiol resin (351) gave polymer-bound thiopyfimidine 355 which was in a preliminary study also obtained from isothiourea 353 and the bis-acceptor reactophor 354. Pyrimidine 355 was cleaved from the resin after oxidation with mCPBA by treatment with amines to yield 2-amino-pyrimidines 356; or 355 was converted into the polymer-supported thiopyfimidines 357,

which after saponification, amide coupling and

subsequent multidirectional cleavage gave 2-aminopyrimidines of type 360.

Alternatively,

pyTimidine 355 was saponified, the resulting acid reduced to the coresponding intermediate alcohol and converted in a Mitsunobu coupling with phenol into polymer-bound ether 358. Oxidation and cleavage with amines resulted in clean formation of 2-aminopyrimidines of type 359. Masquelin et al. 151 took advantage of a similar strategy (Scheme 4.6.9). Thus, polymer-bound

isothiourea 338 (Scheme 4.6.5) was treated with the commercially available bis-acceptor building block 361 to yield cleanly polymer-bound 6-amino-5-cyano-pyrimidine 362. This versatile building block was cleaved after oxidation with m-CPBA with amines to yield diaminopyrimidines of type 363. Scheme 4.6.9

Reagents and conditions: i) DIEA, DMF, z~; ii) m-CPBA, CH2CI2; iii) R1R2NH, CH2CI2or dioxane

The strategies described in Schemes 4.6.5-4.6.9 thus combine efficiently a novel sulfur-based "safety-catch" linker strategy, multigeneration construction of thio-linked pyrimidines with a multidirectional cleavage procedure. This approach should prove successful for the solid-phase synthesis of a whole range of nitrogen-containing heterocycles such as pyrimidines, lriazines, imidazoles, benzimidazoles.

327

4. Convergentassemblystrategieson solid supports

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333

Outlook andfuture directions

Outlook and future directions Combinatorial and parallel synthesis techniques will certainly have an increasing impact in drug discovery as the repertoire of synthetic methods amenable to solid-phase chemistry will expand, leading to more and more complex structures. High throughput methods, however, are by no means limited to the synthesis of compound libraries for screening and have found wide applications in process development and material sciences. 1 In process development where many parameters such as concentrations of reactants, choice of proper solvents, catalysts, reaction temperatures and reaction times have to be optimised, it is believed that combinatorial approaches will allow a simultaneous screening of parameters and thus speed up the development process. Material sciences offer a tremendous platform for combinatorial chemistry in finding novel materials for electronic, magnetic and optical devices. Efficient green, blue and red phosphors2, 3 were discovered using combinatorial techniques. Such approaches have also been used to find new iridium catalysts 4 for alkane dehydrogenation.

References (1) E. K. Wilson, Chem. Eng. News 1997, December 8, 24. (2) E. Danielson, J. H. Golden, E. W. McFarland, C. M. Reaves, W. H. Weinberg and X. D. Wu, Nature 1997, 389, 944. (3) X.-D. Sun, C. Gao, J. Wang and X.-D. Xiang, Appl. Phys. Lett. 1997, 70, 3353. (4) W.-W. Xu, G. P. Rosini, M. Gupta, C. Jensen, W. C. Kaska, K. Krogh-Jespersen and A. S. Goldman, J. Chem. Soc., Chem. Commun. 1997, 2273.

334

Subject Index

Subject Index

o~-alkynyl ketones, 138

benzodiazocines, 247

acceptor molecules, 134

benzoisothiazolones, 307

acceptor-donor molecules, 136

BHA, 89

ACD, 157

bicyclo[2.2.2]octanes, 320

ACE, 279

Biginelli reaction, 120, 223,

acetylenic ketones, 138

304

alanine scan, 188

binary code, 150

alcohols

bioavailability, 188

release of, 94 aldehydes release of, 95 alumina, 44

Bischler-Napieralski reaction,

283

cyclisation-assisted, 85, 96, 318 monofunctional, 85,289 multidirectional, 85, 98, 319 cocktails, 107 combinatorics of building blocks, 130, 142 constraints conformational, 188 convergent, 112

13-1actams, 280

core structure, 15, 112, 127

bromination, 69

coupling agents

Amberlyst, 45

13-turn, 189

Amides

Bucherer-Bergs synthesis, 120

CROSSFIRE, 157

building blocks, 127

cyclisation-assisted. See

release of, 89 Amines

Burgess reagent, 228

release of, 92

polymer-supported, 67

cleavage cycloaddition reaction

amino-2H-azirines, 218

capping reagents, 134

1,3-dipolar, 278

analytical methods, 158

Carbonyl-Alkyne-Exchange

1,3-dipolar, 302

angiotensin converting enzyme, 86 asymmetric dihydroxylation, 74, 235 Atwal reaction, 121

avermectin, 20

reactions, 139 carboxylic acids

cyclohexane, 321 cyclopentane, 321

release of, 86 cascade reactions, 123

data management, 18

catalysts

Davies reagent, 97

polymer-supported, 73, 216

deconvolution, 112, 145

aza-Diels-Alder reaction, 240

Ceclor, 86

aza-Wittig reaction, 247

cellulose, 201,253

azlactone, 120

chaperone, 17 charge distribution, 156

dialysis, 253

BAL, 93

chiral auxiliaries, 79

Diels-Alder reaction, 240

bases

chlorination, 69

diketopiperazines, 318

Ciproxin, 86

diols

polymer-supported, 70

dehydrating agents polymer-supported, 67 dendrimers, 24, 243

benzimidazoles, 259

CLEAR, 42

release of, 94

benzodiazepines, 247, 262, 287,

cleavage, 85

dipole moment, 156

292, 306

diversification, 127

335

Subject Index

diversity, 107, 156

graphite, 44

Diversomerr 25

guanidines

divinylbenzene, 27

release of, 95

Doebner reaction, 303

focused, 107 random, 107

domino reactions, 123

halogen-carriers, 69

donor building blocks, 131

Hantzsch multicomponent

drug discovery, 17

optimisation, 20 libraries

condensation, 119, 226, 271

taylor-made, 107 library, 15 linear, 112

drug-like, 127

HIV-proteinase, 17

DVB, 27

HMB, 89

linker, 85

Horner-Emmons reaction, 134

lipophilicity, 156

Horner-Wittig reaction, 62

Liquid-phase combinatorial

electrophiles solid-supported, 63

Hycram, 88

synthesis, 11

synthesis, 255

ELISA, 187

hydantoins, 120, 310, 312

LPCS, 255

encoding, 149

hydroxamic acids

LPE, 213

ensemble, 15

release of, 91

enzyme, 17

macrocyclisations, 44

epitope mapping, 186

imidazoles, 300

macroporous, 28

epoxidation, 74, 237

immobilisation

magic-angle spinning NMR,

Erlenmeyer azlactone synthesis,

120 Evans oxazolidinone, 81,230

of catalysts, 26, 60

159

of reagents, 26, 44, 60

MALDI-TOF, 158

of substrates, 24

Mannich reaction, 120

indole, 124

material sciences, 334

liquid-liquid, 213,222

intermediate catch, 246

matrix metaUoproteinases, 91

liquid-solid, 213,225

ion exchange resins, 35, 45

MBHA, 89

lreland-Claisen rearrangement,

Meldrum's acid, 308

extractions

filamentous phage, 186 FK506, 20

125 isoquinolines

Merrifield resin, 30, 87 microporous, 27

flavoridin, 195

dihydro, 283

mimetics, 190

fluorinated solvents, 222

tetrahydro, 283

mimotope strategy, 187

furans, 296

iterative deconvolufion, 145

3-halo-, 139

gel permeation chromatography,

mitomycin, 20 Kaiser resin, 90

Mitsunobu reaction, 77, 232

Knoevenagel condensation, 272

MMP's, 91

253 gel-phase NMR, 159 genetic algorithm, 217 glucose, 201

modular approach, 23 Lalibert~ thiophene synthesis,

290 lead

glycal method, 201

finding, 17

GPIIb/IIIa, 195

natural products, 20

336

miniaturisation, 18

modulator, 17 Moffatt oxidation, 67

monensin, 20 monofunctional. See cleavage

Subject Index

Mukaiyama aldol reaction, 74,

Pauson-Khand reaction, 122

mercaptoacyl, 278

PEG, 39

prostaglandins, 298

PEGA, 40

protective groups, 44, 251

peptide-nucleic acids, 207

purification, 54

multidirectional. See cleavage

peptides, 186

purines, 273

multigeneration reactions, 114,

peptidomimetic, 18

pyrazoles, 140, 227, 234

peptoids, 197

pyrazolones, 308

multipin synthesis, 187

pharmacophor, 127

pyridines, 277

multiple release, 155

phase transfer catalysts, 44

multipolymer systems, 49, 234

phenols

239 multicomponent reactions, 114, 117, 142

123

mtinchnone, 219

release of, 94 phosphite triester, 200

Naproxen, 86

photocleavable linker, 87

nitroaldol reaction, 70

phthalazinones

NMR gel-phase, 159 magic-angle spinning, 159 nucleophiles solid-supported, 61

release of, 95

dihydro, 119 dihydro, 271 pyrimidines, 323 dihydro, 121 dihydro, 304 pyrroles, 119 pyrrolidines, 265

pins, 26 plasmids, 186 PNA, 207

quinazolin-2,4-diones, 261, 281, 313

POEPOP, 42

quinazolinones, 316

POEPS, 42

quinolines, 139

oligocarbamates, 205

polyacrylamide, 38,253

oligonucleotides, 11,200

polyethyleneglycol, 39

oligosaccharides, 201,254

polyethylenglycol, 253

oligoureas, 205

polymers

tetrahydro-, 122, 245 quinolinones dihydro, 284 quinolones, 275

Olomoucine, 273

crosslinked, 24

one-pot, 114

dendrimeric, 10

optimisation

inorganic, 24

lead, 20

insoluble, 49

rational drug design, 18

linear, 24

REACCS, 157

soluble, 52, 252

reactophor, 127

orthogonal libraries, 148 oxazaborolidines, 238 oxazoles, 121

polypeptides, 11

oxidants

polystyrene, 25

solid-supported, 64 oxidation, 64

quinoxalinones tetrahydro, 285

reagents explosive, 14

aminomethylated, 32

solid-supported, 10, 216

chloromethylated, 30

unstable, 14

polyvinylalcohol, 253

receptor, 14, 17

PAL, 274

porantherine, 120

recognition, 201

PAM, 87

positional scanning, 147

recursive deconvolution, 146

parallel format, 10

process development, 334

reducing agents

Passerini reaction, 118, 121

prolines, 302

polymer-supported, 66 337

Subject Index

reduction, 66

strategies

thioureas cyclic, 269

resin capture, 246

convergent, 112

retro-inverso, 189

linear, 112, 185

traceless linkers, 85,292

Rink-amide, 89

synthetic, 105

transcription factor, 17

Rink-chloride, 93

Strecker synthesis, 119

trap, 13, 57

Rink-resin, 87

sulfonamides

triazoles, 289

robotic systems, 160

release of, 90 supports

safety-catch linker, 85, 101,322

triphenylphosphine, 231 trityl resin, 87

solid, 24

Sasrin-resin, 87

Suzuki-couplings, 249

Ugi-4CC, 117, 218, 246

SCAL, 89

swelling capacity, 28

unnatural amino acids, 189

scavenger, 57, 63, 105, 215,

synthesis

ureas

224 screening, 107

combinatorial, 15

cyclic, 269

parallel, 15 Vasotech, 86

high throughput, 18 TADDOL, 242

virtual library, 156

Sharpless epoxidation, 237

tag, 145

Voltaren, 86

silica, 44

tagging, 112, 145

single compound collections,

tamoxifen, 250

Wang-resin, 87

random, 18

tandem reactions, 123

Weinreb amide, 139

solid-phase chemistry, 105

taxol, 20, 153

Wilkinson's catalyst, 54

solution-phase chemistry, 105

tea bags, 25

Wittig reaction, 72, 134, 231

SPE, 213

tea-bag method, 187

Wittig-Horner reaction, 220

split and combine, 108

TentaGel, 39

workstations, 160

split-mixed synthesis, 108

thiazoles, 119, 220, 226

106

starch, 201

Staudinger reaction, 232 Stille coupling, 223, 264

338

dihydro, 290 thiophenes, 290 3-bromo-, 139

zeolites, 44

Acknowledgements

The authors would like to thank: Profs. Drs. Heinz Heimgartner and John A. Robinson (University of Ziirich, CH) for proof-reading the manuscript; Sir Jack Baldwin (Waynflete Professor of Chemistry, Oxford, UK), Prof. Dr. Andrea Vasella (ETH Ziirich, CH) and Dr. JeanPierre Obrecht (Polyphor Ltd., ZUrich, CH) for many stimulating discussions; Dr. Alexander Chucholowski (F. Hoffmann-La Roche Ltd.) for his excellent contribution; Mr. Werner Doebelin (Prolab/LabSource, Reinach, CH) for providing Figure 1.13 and for his technical assistance; Mrs. Liza Koltay (Koltay Design, Bottmingen, CH) for the cover-art and Dr. Cornelia Zumbrunn for the preparation of the final camera-ready manuscript. DO would like to thank Mrs. Patricia Bir and Mrs. Jeanne Obrecht for their constant support and motivation.

339


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